dyslipidemia, and weight gain€¦ · • Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. Appropriate clinical monitoring

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SEROQUEL safely and effectively See full prescribing information for SEROQUEL

SEROQUELreg (quetiapine) tablets for oral use Initial US Approval 1997

WARNING INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL

THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning

Increased Mortality in Elderly Patients with Dementia-Related Psychosis bull Elderly patients with dementia-related psychosis treated with

antipsychotic drugs are at an increased risk of death SEROQUEL is not approved for elderly patients with dementia-related psychosis (51)

Suicidal Thoughts and Behaviors bull Increased risk of suicidal thoughts and behavior in children

adolescents and young adults taking antidepressants (52) bull Monitor for worsening and emergence of suicidal thoughts and

behaviors (52)

-------------------------- RECENT MAJOR CHANGES -------------------------shyWarnings and Precautions Tardive Dyskinesia (56) 082019

--------------------------- INDICATIONS AND USAGE -------------------------shySEROQUEL is an atypical antipsychotic indicated for the treatment of bull Schizophrenia (11) bull Bipolar I disorder manic episodes (12) bull Bipolar disorder depressive episodes (12)

---------------------- DOSAGE AND ADMINISTRATION ---------------------shybull SEROQUEL can be taken with or without food (21) Indication Initial Dose Recommended

Dose Maximum

Dose Schizophrenia shyAdults (22)

25 mg twice daily

150-750 mgday 750 mgday

Schizophrenia shyAdolescents (13-17 years) (22)

25 mg twice daily


Bipolar Mania shyAdults Monotherapy or as an adjunct to lithium or divalproex (22)

50 mg twice daily

400ndash 800 mgday

800 mgday

Bipolar Mania shyChildren and Adolescents (10-17 years) Monotherapy (22)

25 mg twice daily


Bipolar Depression shyAdults (22)

50 mg once daily at bedtime

300 mgday 300 mgday

bull Geriatric Use Consider a lower starting dose (50 mgday) slower titration and careful monitoring during the initial dosing period in the elderly (23 85)

bull Hepatic Impairment Lower starting dose (25 mgday) and slower titration may be needed (24 87 123)

--------------------- DOSAGE FORMS AND STRENGTHS -------------------shyTablets 25 mg 50 mg 100 mg 200 mg 300 mg and 400 mg (3)

------------------------------ CONTRAINDICATIONS ----------------------------shyKnown hypersensitivity to SEROQUEL or any components in the formulation (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------------shybull Cerebrovascular Adverse Reactions Increased incidence of

cerebrovascular adverse reactions (eg stroke transient ischemic attack)

has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs (53)

bull Neuroleptic Malignant Syndrome (NMS) Manage with immediate discontinuation and close monitoring (54)

bull Metabolic Changes Atypical antipsychotics have been associated with metabolic changes These metabolic changes include hyperglycemia dyslipidemia and weight gain (55) bull Hyperglycemia and Diabetes Mellitus Monitor patients for

symptoms of hyperglycemia including polydipsia polyuria polyphagia and weakness Monitor glucose regularly in patients with diabetes or at risk for diabetes

bull Dyslipidemia Undesirable alterations have been observed in patients treated with atypical antipsychotics Appropriate clinical monitoring is recommended including fasting blood lipid testing at the beginning of and periodically during treatment

bull Weight Gain Gain in body weight has been observed clinical monitoring of weight is recommended

bull Tardive Dyskinesia Discontinue if clinically appropriate (56) bull Hypotension Use with caution in patients with known cardiovascular or

cerebrovascular disease (57) bull Increased Blood Pressure in Children and Adolescents Monitor blood

pressure at the beginning of and periodically during treatment in children and adolescents (59)

bull Leukopenia Neutropenia and Agranulocytosis Monitor complete blood count frequently during the first few months of treatment in patients with a pre-existing low white cell count or a history of leukopenianeutropenia and discontinue SEROQUEL at the first sign of a decline in WBC in absence of other causative factors (510)

bull Cataracts Lens changes have been observed in patients during long-term quetiapine treatment Lens examination is recommended when starting treatment and at 6-month intervals during chronic treatment (511)

bull Anticholinergic(antimuscarinic) Effects Use with caution with other anticholinergic drugs and in patients with urinary retention prostatic hypertrophy constipation and increased intraocular pressure (520)

------------------------------ ADVERSE REACTIONS ----------------------------shybull Most common adverse reactions (incidence ge5 and twice placebo)

Adults somnolence dry mouth dizziness constipation asthenia abdominal pain postural hypotension pharyngitis weight gain lethargy ALT increased dyspepsia (61)

bull Children and Adolescents somnolence dizziness fatigue increased appetite nausea vomiting dry mouth tachycardia weight increased (61)

To report SUSPECTED ADVERSE REACTIONS contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or wwwfdagovmedwatch

------------------------------ DRUG INTERACTIONS ----------------------------shybull Concomitant use of strong CYP3A4 inhibitors Reduce quetiapine dose

to one sixth when coadministered with strong CYP3A4 inhibitors (eg ketoconazole ritonavir) (25 7 1 12 3)

bull Concomitant use of strong CYP3A4 inducers Increase quetiapine dose up to 5 fold when used in combination with a chronic treatment (more than 7-14 days) of potent CYP3A4 inducers (eg phenytoin rifampin St Johnrsquos wort) (26 71 123)

bull Discontinuation of strong CYP3A4 inducers Reduce quetiapine dose by 5 fold within 7-14 days of discontinuation of CYP3A4 inducers (26 71 123)

----------------------- USE IN SPECIFIC POPULATIONS ---------------------shybull Pregnancy May cause extrapyramidal andor withdrawal symptoms in

neonates with third trimester exposure (81)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide

Revised 032020

FULL PRESCRIBING INFORMATION CONTENTS

WARNING INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS AND SUICIDAL THOUGHTS AND BEHAVIORS 1 INDICATIONS AND USAGE

11 Schizophrenia 12 Bipolar Disorder 13 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder

2 DOSAGE AND ADMINISTRATION 21 Important Administration Instructions 22 Recommended Dosing 23 Dose Modifications in Elderly Patients 24 Dose Modifications in Hepatically Impaired Patients 25 Dose Modifications when used with CYP3A4 Inhibitors 26 Dose Modifications when used with CYP3A4 Inducers 27 Re-initiation of Treatment in Patients Previously Discontinued 28 Switching from Antipsychotics

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

51 Increased Mortality in Elderly Patients with Dementia-Related Psychosis 52 Suicidal Thoughts and Behaviors in Adolescents and Young Adults 53 Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis 54 Neuroleptic Malignant Syndrome (NMS) 55 Metabolic Changes 56 Tardive Dyskinesia 57 Hypotension 58 Falls 59 Increases in Blood Pressure (Children and Adolescents) 510 Leukopenia Neutropenia and Agranulocytosis 511 Cataracts 512 QT Prolongation 513 Seizures 514 Hypothyroidism 515 Hyperprolactinemia 516 Potential for Cognitive and Motor Impairment

517 Body Temperature Regulation 518 Dysphagia 519 Discontinuation Syndrome 520 Anticholinergic (antimuscarinic) Effects

6 ADVERSE REACTIONS 61 Clinical Study Experience 62 Postmarketing Experience

7 DRUG INTERACTIONS 71 Effect of Other Drugs on Quetiapine 72 Effect of Quetiapine on Other Drugs

8 USE IN SPECIFIC POPULATIONS 81 Pregnancy 82 Lactation 83 Females and Males of Reproductive Potential 84 Pediatric Use 85 Geriatric Use 86 Renal Impairment 87 Hepatic Impairment

9 DRUG ABUSE AND DEPENDENCE 91 Controlled Substance 92 Abuse

10 OVERDOSAGE 101 Human Experience 102 Management of Overdosage

11 DESCRIPTION 12 CLINICAL PHARMACOLOGY

121 Mechanism of Action 122 Pharmacodynamics 123 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY 131 Carcinogenesis Mutagenesis Impairment of Fertility 132 Animal Toxicology andor Pharmacology

14 CLINICAL STUDIES 141 Schizophrenia 142 Bipolar Disorder

16 HOW SUPPLIEDSTORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed

FULL PRESCRIBING INFORMATION

WARNING INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS

Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death [see Warnings and Precautions (51)] SEROQUEL is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (51)]

Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in children adolescents and young adults in short-term studies These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24 there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (52)] In patients of all ages who are started on antidepressant therapy monitor closely for worsening and for emergence of suicidal thoughts and behaviors Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (52)]

SEROQUEL is not approved for use in pediatric patients under ten years of age [see Use in Specific Populations (84)]

1 INDICATIONS AND USAGE

11 Schizophrenia SEROQUEL is indicated for the treatment of schizophrenia The efficacy of SEROQUEL in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents (13-17 years) The effectiveness of SEROQUEL for the maintenance treatment of schizophrenia has not been systematically evaluated in controlled clinical trials [see Clinical Studies (141)]

12 Bipolar Disorder SEROQUEL is indicated for the acute treatment of manic episodes associated with bipolar I disorder both as monotherapy and as an adjunct to lithium or divalproex Efficacy was established in two 12-week monotherapy trials in adults in one 3-week adjunctive trial in adults and in one 3-week monotherapy trial in pediatric patients (10-17 years) [see Clinical Studies (142)]

SEROQUEL is indicated as monotherapy for the acute treatment of depressive episodes associated with bipolar disorder Efficacy was established in two 8-week monotherapy trials in adult patients with bipolar I and bipolar II disorder [see Clinical Studies (142)]

SEROQUEL is indicated for the maintenance treatment of bipolar I disorder as an adjunct to lithium or divalproex Efficacy was established in two maintenance trials in adults The effectiveness of SEROQUEL as monotherapy for the maintenance treatment of bipolar disorder has not been systematically evaluated in controlled clinical trials [see Clinical Studies (142)]

13 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder Pediatric schizophrenia and bipolar I disorder are serious mental disorders however diagnosis can be challenging For pediatric schizophrenia symptom profiles can be variable and for bipolar I disorder patients may have variable patterns of periodicity of manic or mixed symptoms It is recommended that medication therapy for pediatric schizophrenia and

bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment Medication treatment for both pediatric schizophrenia and bipolar I disorder is indicated as part of a total treatment program that often includes psychological educational and social interventions

2 DOSAGE AND ADMINISTRATION

21 Important Administration Instructions SEROQUEL can be taken with or without food

22 Recommended Dosing The recommended initial dose titration dose range and maximum SEROQUEL dose for each approved indication is displayed in Table 1 After initial dosing adjustments can be made upwards or downwards if necessary depending upon the clinical response and tolerability of the patient [see Clinical Studies (141 and 142)]

Table 1 Recommended Dosing for SEROQUEL

Indication Initial Dose and Titration Recommended Dose Maximum Dose Schizophrenia - Adults Day 1 25 mg twice daily

Increase in increments of 25 mg-50 mg divided two or three times on Days 2 and 3 to range of 300-400 mg by Day 4 Further adjustments can be made in increments of 25-50 mg twice a day in intervals of not less than 2 days


Schizophrenia - Adolescents (13-17 years)

Day 1 25 mg twice daily Day 2 Twice daily dosing totaling 100 mg Day 3 Twice daily dosing totaling 200 mg Day 4 Twice daily dosing totaling 300 mg Day 5 Twice daily dosing totaling 400 mg Further adjustments should be in increments no greater than 100 mgday within the recommended dose range of 400-800 mgday Based on response and tolerability may be administered three times daily


Schizophrenia shyMaintenance

Not applicable 400-800 mgday 800 mgday

Bipolar Mania - Adults Day 1 Twice daily dosing 400-800 mgday 800 mgday

Monotherapy or as an totaling 100 mg adjunct to lithium or Day 2 Twice daily dosing divalproex totaling 200 mg

Day 3 Twice daily dosing totaling 300 mg Day 4 Twice daily dosing totaling 400 mg Further dosage adjustments up to 800 mgday by Day 6 should be in increments of no greater than 200 mgday

Bipolar Mania - Children Day 1 25 mg twice daily 400-600 mgday 600 mgday and Adolescents (10 to 17 Day 2 Twice daily dosing years) Monotherapy totaling 100 mg

Day 3 Twice daily dosing totaling 200 mg Day 4 Twice daily dosing totaling 300 mg Day 5 Twice daily dosing totaling 400 mg Further adjustments should be in increments no greater than 100 mgday within the recommended dose range of 400-600 mgday Based on response and tolerability may be administered three times daily

Bipolar Depression - Adults Administer once daily at bedtime Day 1 50 mg Day 2 100 mg Day 3 200 mg Day 4 300 mg

300 mgday 300 mgday

Bipolar I Disorder Maintenance Therapy shyAdults

Administer twice daily totaling 400-800 mgday as adjunct to lithium or divalproex Generally in the maintenance phase patients continued on the same dose on which they were stabilized


Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatment ndash Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (142)]

23 Dose Modifications in Elderly Patients Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [see Clinical Pharmacology (123)] When indicated dose escalation should be performed with caution in these patients

Elderly patients should be started on SEROQUEL 50 mgday and the dose can be increased in increments of 50 mgday depending on the clinical response and tolerability of the individual patient

24 Dose Modifications in Hepatically Impaired Patients Patients with hepatic impairment should be started on 25 mgday The dose should be increased daily in increments of 25 mgday - 50 mgday to an effective dose depending on the clinical response and tolerability of the patient

25 Dose Modifications when used with CYP3A4 Inhibitors SEROQUEL dose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (eg ketoconazole itraconazole indinavir ritonavir nefazodone etc) When the CYP3A4 inhibitor is discontinued the dose of SEROQUEL should be increased by 6-fold [see Clinical Pharmacology (123) and Drug Interactions (71)]

26 Dose Modifications when used with CYP3A4 Inducers SEROQUEL dose should be increased up to 5-fold of the original dose when used in combination with a chronic treatment (eg greater than 7-14 days) of a potent CYP3A4 inducer (eg phenytoin carbamazepine rifampin avasimibe St Johnrsquos wort etc) The dose should be titrated based on the clinical response and tolerability of the individual patient When the CYP3A4 inducer is discontinued the dose of SEROQUEL should be reduced to the original level within 7-14 days [see Clinical Pharmacology (123) and Drug Interactions (71)]

27 Re-initiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address re-initiation of treatment it is recommended that when restarting therapy of patients who have been off SEROQUEL for more than one-week the initial dosing schedule should be followed When restarting patients who have been off SEROQUEL for less than one-week gradual dose escalation may not be required and the maintenance dose may be re-initiated

28 Switching from Antipsychotics There are no systematically collected data to specifically address switching patients with schizophrenia from antipsychotics to SEROQUEL or concerning concomitant administration with antipsychotics While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia more gradual discontinuation may be most appropriate for others In all cases the period of overlapping antipsychotic administration should be minimized When switching patients with schizophrenia from depot antipsychotics if medically appropriate initiate SEROQUEL therapy in place of the next scheduled injection The need for continuing existing EPS medication should be re-evaluated periodically

3 DOSAGE FORMS AND STRENGTHS

bull 25 mg tablets are peach round biconvex film coated tablets identified with SEROQUEL and lsquo25rsquo on one side and plain on the other side

bull 50 mg tablets are white round biconvex film coated tablets identified with SEROQUEL and lsquo50rsquo on one side and plain on the other side

bull 100 mg tablets are yellow round biconvex film coated tablets identified with SEROQUEL and lsquo100rsquo on one side and plain on the other side

bull 200 mg tablets are white round biconvex film coated tablets identified with lsquoSEROQUELrsquo and lsquo200rsquo on one side and plain on the other side

bull 300 mg tablets are white capsule-shaped biconvex film coated tablets intagliated with lsquoSEROQUELrsquo on one side and lsquo300rsquo on the other side

bull 400 mg tablets are yellow capsule-shaped biconvex film coated tablets intagliated with lsquoSEROQUELrsquo on one side and lsquo400rsquo on the other side

4 CONTRAINDICATIONS

Hypersensitivity to quetiapine or to any excipients in the SEROQUEL formulation Anaphylactic reactions have been reported in patients treated with SEROQUEL

5 WARNINGS AND PRECAUTIONS

51 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death Analysis of 17 placebo-controlled trials (modal duration of 10 weeks) largely in patients taking atypical antipsychotic drugs revealed a risk of death in drug-treated patients of between 16 to 17 times the risk of death in placebo-treated patients Over the course of a typical 10-week controlled trial the rate of death in drug-treated patients was about 45 compared to a rate of about 26 in the placebo group Although the causes of death were varied most of the deaths appeared to be either cardiovascular (eg heart failure sudden death) or infectious (eg pneumonia) in nature Observational studies suggest that similar to atypical antipsychotic drugs treatment with conventional antipsychotic drugs may increase mortality The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear SEROQUEL is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning]

52 Suicidal Thoughts and Behaviors in Adolescents and Young Adults Patients with major depressive disorder (MDD) both adult and pediatric may experience worsening of their depression andor the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior whether or not they are taking antidepressant medications and this risk may persist until significant remission occurs Suicide is a known risk of depression and certain other psychiatric disorders and these disorders themselves are the strongest predictors of suicide There has been a long-standing concern however that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children adolescents and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24 there was a reduction with antidepressants compared to placebo in adults aged 65 and older

The pooled analyses of placebo-controlled trials in children and adolescents with MDD obsessive-compulsive disorder (OCD) or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77000 patients There was considerable variation in risk of suicidality among drugs but a tendency toward an increase in the younger patients for almost all drugs studied There were differences in absolute risk of suicidality across the different indications with the highest incidence in MDD The risk differences (drug vs placebo) however were relatively stable within age strata and across indications These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2

Table 2 Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated

Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo

lt18 14 additional cases

18-24 5 additional cases

Decreases Compared to Placebo

25-64 1 fewer case

ge65 6 fewer cases

No suicides occurred in any of the pediatric trials There were suicides in the adult trials but the number was not sufficient to reach any conclusion about drug effect on suicide

It is unknown whether the suicidality risk extends to longer-term use ie beyond several months However there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening suicidality and unusual changes in behavior especially during the initial few months of a course of drug therapy or at times of dose changes either increases or decreases

The following symptoms anxiety agitation panic attacks insomnia irritability hostility aggressiveness impulsivity akathisia (psychomotor restlessness) hypomania and mania have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications both psychiatric and non-psychiatric Although a causal link between the emergence of such symptoms and either the worsening of depression andor the emergence of suicidal impulses has not been established there is concern that such symptoms may represent precursors to emerging suicidality

Consideration should be given to changing the therapeutic regimen including possibly discontinuing the medication in patients whose depression is persistently worse or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality especially if these symptoms are severe abrupt in onset or were not part of the patients presenting symptoms

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications both psychiatric and non-psychiatric should be alerted about the need to monitor patients for the emergence of agitation irritability unusual changes in behavior and the other symptoms described above as well as the emergence of suicidality and to report such symptoms immediately to healthcare providers Such monitoring should include daily observation by families and caregivers Prescriptions for SEROQUEL should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose

Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixedmanic episode in patients at risk for bipolar disorder Whether any of the symptoms described above represent such a conversion is unknown However prior to initiating treatment with an antidepressant including SEROQUEL patients with depressive symptoms should be adequately

screened to determine if they are at risk for bipolar disorder such screening should include a detailed psychiatric history including a family history of suicide bipolar disorder and depression

53 Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone aripiprazole and olanzapine in elderly subjects with dementia there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects SEROQUEL is not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (51)]

54 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs including SEROQUEL Rare cases of NMS have been reported with SEROQUEL Clinical manifestations of NMS are hyperpyrexia muscle rigidity altered mental status and evidence of autonomic instability (irregular pulse or blood pressure tachycardia diaphoresis and cardiac dysrhythmia) Additional signs may include elevated creatinine phosphokinase myoglobinuria (rhabdomyolysis) and acute renal failure

The diagnostic evaluation of patients with this syndrome is complicated In arriving at a diagnosis it is important to exclude cases where the clinical presentation includes both serious medical illness (eg pneumonia systemic infection etc) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS) Other important considerations in the differential diagnosis include central anticholinergic toxicity heat stroke drug fever and primary central nervous system (CNS) pathology

The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy 2) intensive symptomatic treatment and medical monitoring and 3) treatment of any concomitant serious medical problems for which specific treatments are available There is no general agreement about specific pharmacological treatment regimens for NMS

If a patient requires antipsychotic drug treatment after recovery from NMS the potential reintroduction of drug therapy should be carefully considered The patient should be carefully monitored since recurrences of NMS have been reported

55 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemiadiabetes mellitus dyslipidemia and body weight gain While all of the drugs in the class have been shown to produce some metabolic changes each drug has its own specific risk profile In some patients a worsening of more than one of the metabolic parameters of weight blood glucose and lipids was observed in clinical studies Changes in these metabolic profiles should be managed as clinically appropriate

Hyperglycemia and Diabetes Mellitus Hyperglycemia in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death has been reported in patients treated with atypical antipsychotics including quetiapine Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population Given these confounders the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood However epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control Patients with risk factors for diabetes mellitus (eg obesity family history of

diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia polyuria polyphagia and weakness Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing In some cases hyperglycemia has resolved when the atypical antipsychotic was discontinued however some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug

Adults

Table 3 Fasting Glucose ndash Proportion of Patients Shifting to ge126 mgdL in Short-Term (le12 weeks) Placebo-Controlled Studies1

Laboratory Analyte

Category Change (At Least Once) from Baseline

Treatment Arm N Patients n ()

Normal to High (lt100 mgdL to

Quetiapine 2907 71 (24)

Fasting Glucose

ge126 mgdL) Placebo 1346 19 (14)

Borderline to High (ge100 mgdL and lt126 mgdL to ge126 mgdL)


Placebo 279 33 (118)

1 Includes SEROQUEL and SEROQUEL XR data

In a 24-week trial (active-controlled 115 patients treated with SEROQUEL) designed to evaluate glycemic status with oral glucose tolerance testing of all patients at Week 24 the incidence of a post-glucose challenge glucose level ge200 mgdL was 17 and the incidence of a fasting blood glucose level ge126 mgdL was 26 The mean change in fasting glucose from baseline was 32 mgdL and mean change in 2-hour glucose from baseline was -18 mgdL for quetiapine

In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar I disorder maintenance mean exposure of 213 days for SEROQUEL (646 patients) and 152 days for placebo (680 patients) the mean change in glucose from baseline was +50 mgdL for SEROQUEL and ndash005 mgdL for placebo The exposure-adjusted rate of any increased blood glucose level (ge126 mgdL) for patients more than 8 hours since a meal (however some patients may not have been precluded from calorie intake from fluids during fasting period) was 180 per 100 patient years for SEROQUEL (107 of patients n=556) and 95 for placebo per 100 patient years (46 of patients n=581)

Children and Adolescents In a placebo-controlled SEROQUEL monotherapy study of adolescent patients (13-17 years of age) with schizophrenia (6 weeks duration) the mean change in fasting glucose levels for SEROQUEL (n=138) compared to placebo (n=67) was ndash 075 mgdL versus ndash170 mgdL In a placebo-controlled SEROQUEL monotherapy study of children and adolescent patients (10-17 years of age) with bipolar mania (3 weeks duration) the mean change in fasting glucose level for SEROQUEL (n=170) compared to placebo (n=81) was 362 mgdL versus ndash117 mgdL No patient in either study with a baseline normal fasting glucose level (lt100 mgdL) or a baseline borderline fasting glucose level (ge100 mgdL and lt126 mgdL) had a blood glucose level of ge126 mgdL

In a placebo-controlled SEROQUEL XR monotherapy study (8 weeks duration) of children and adolescent patients (10shy17 years of age) with bipolar depression in which efficacy was not established the mean change in fasting glucose levels for SEROQUEL XR (n=60) compared to placebo (n=62) was 18 mgdL versus 16 mgdL In this study there were no patients in the SEROQUEL XR or placebo-treated groups with a baseline normal fasting glucose level (lt100 mgdL) that had an increase in blood glucose level gt126 mgdL There was one patient in the SEROQUEL XR group with a baseline

borderline fasting glucose level (gt100 mgdL and lt126 mgdL) who had an increase in blood glucose level of gt126 mgdL compared to zero patients in the placebo group

Dyslipidemia

Adults Table 4 shows the percentage of adult patients with changes in total cholesterol triglycerides LDL-cholesterol and HDL-cholesterol from baseline by indication in clinical trials with SEROQUEL

Table 4 Percentage of Adult Patients with Shifts in Total Cholesterol Triglycerides LDL-Cholesteroland HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication

Laboratory Analyte

Indication Treatment Arm N Patients n ()

Total Cholesterol ge240 mgdL

Schizophrenia1 SEROQUEL 137 24 (18)

Placebo 92 6 (7)

Bipolar Depression2

SEROQUEL 463 41 (9)

Placebo 250 15 (6)

Triglycerides ge200 mgdL


Placebo 70 11 (16)

Bipolar Depression2

SEROQUEL 436 59 (14)

Placebo 232 20 (9)

LDL-Cholesterol ge160 mgdL

Schizophrenia1 SEROQUEL na3 na3

Placebo na3 na3

Bipolar Depression2

SEROQUEL 465 29 (6)

Placebo 256 12 (5)

HDL-Cholesterol le40 mgdL


Placebo na3 na3

Bipolar Depression2


Placebo 214 29 (14) 1 6 weeks duration 2 8 weeks duration 3 Parameters not measured in the SEROQUEL registration studies for schizophrenia

Children and Adolescents Table 5 shows the percentage of children and adolescents with changes in total cholesterol triglycerides LDL-cholesterol and HDL-cholesterol from baseline in clinical trials with SEROQUEL

Table 5 Percentage of Children and Adolescents with Shifts in Total Cholesterol Triglycerides LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels

Laboratory Analyte



Schizophrenia1 SEROQUEL 107 13 (12) Placebo 56 1 (2)

Bipolar Mania2 SEROQUEL 159 16 (10)

Placebo 66 2 (3)



Bipolar Mania2 SEROQUEL 149 32 (22) Placebo 60 8 (13)







1 13-17 years 6 weeks duration 2 10-17 years 3 weeks duration

In a placebo-controlled SEROQUEL XR monotherapy study (8 weeks duration) of children and adolescent patients (10shy17 years of age) with bipolar depression in which efficacy was not established the percentage of children and adolescents with shifts in total cholesterol (ge200 mgdL) triglycerides (ge150 mgdL) LDL-cholesterol (ge 130 mgdL) and HDL-cholesterol (le40 mgdL) from baseline to clinically significant levels were total cholesterol 8 (783) for SEROQUELXR vs 6 (584) for placebo triglycerides 28 (2280) for SEROQUEL XR vs 9 (782) for placebo LDL-cholesterol 2 (286) for SEROQUEL XR vs 4 (385) for placebo and HDL-cholesterol 20 (1365) for SEROQUEL XR vs 15 (1174) for placebo

Weight Gain Increases in weight have been observed in clinical trials Patients receiving quetiapine should receive regular monitoring of weight

Adults In clinical trials with SEROQUEL the following increases in weight have been reported

Table 6 Proportion of Patients with Weight Gain ge7 of Body Weight (Adults)

Vital Sign Indication Treatment Arm N Patients

n () SEROQUEL 391 89 (23)

Schizophrenia1

Placebo 206 11 (6)

Weight Gain ge7 of Body

Weight

Bipolar Mania (monotherapy)2


Placebo 198 13 (7)

Bipolar Mania (adjunct therapy)3


Placebo 203 8 (4)

Bipolar Depression4 SEROQUEL 554 47 (8)

Placebo 295 7 (2)

1 up to 6 weeks duration 2 up to 12 weeks duration 3 up to 3 weeks duration 4 up to 8 weeks duration

Children and Adolescents In two clinical trials with SEROQUEL one in bipolar mania and one in schizophrenia reported increases in weight are included in Table 7

Table 7 Proportion of Patients with Weight Gain ge7 of Body Weight (Children and Adolescents)


n ()



Placebo 44 3 (7)

SEROQUEL 157 18 (12) Weight Bipolar Mania2

Placebo 68 0 (0) 1 6 weeks duration 2 3 weeks duration

The mean change in body weight in the schizophrenia trial was 20 kg in the SEROQUEL group and -04 kg in the placebo group and in the bipolar mania trial it was 17 kg in the SEROQUEL group and 04 kg in the placebo group

In an open-label study that enrolled patients from the above two pediatric trials 63 of patients (241380) completed 26 weeks of therapy with SEROQUEL After 26 weeks of treatment the mean increase in body weight was 44 kg Forty-five percent of the patients gained ge7 of their body weight not adjusted for normal growth In order to adjust for normal growth over 26 weeks an increase of at least 05 standard deviation from baseline in BMI was used as a measure of a clinically significant change 183 of patients on SEROQUEL met this criterion after 26 weeks of treatment

In a clinical trial for SEROQUEL XR in children and adolescents (10-17 years of age) with bipolar depression in which efficacy was not established the percentage of patients with weight gain ge7 of body weight at any time was 15 (1492) for SEROQUEL XR vs 10 (10100) for placebo The mean change in body weight was 14 kg in the SEROQUEL XR group vs 06 kg in the placebo group

When treating pediatric patients with SEROQUEL for any indication weight gain should be assessed against that expected for normal growth

56 Tardive Dyskinesia A syndrome of potentially irreversible involuntary dyskinetic movements may develop in patients treated with antipsychotic drugs including quetiapine Although the prevalence of the syndrome appears to be highest among the elderly especially elderly women it is impossible to rely upon prevalence estimates to predict at the inception of antipsychotic treatment which patients are likely to develop the syndrome Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase However the syndrome can develop although much less commonly after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment

Tardive dyskinesia may remit partially or completely if antipsychotic treatment is withdrawn Antipsychotic treatment itself however may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly

mask the underlying process The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown

Given these considerations SEROQUEL should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs and (2) for whom alternative equally effective but potentially less harmful treatments are not available or appropriate In patients who do require chronic treatment the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought The need for continued treatment should be reassessed periodically

If signs and symptoms of tardive dyskinesia appear in a patient on SEROQUEL drug discontinuation should be considered However some patients may require treatment with SEROQUEL despite the presence of the syndrome

57 Hypotension Quetiapine may induce orthostatic hypotension associated with dizziness tachycardia and in some patients syncope especially during the initial dose-titration period probably reflecting its α1-adrenergic antagonist properties Syncope was reported in 1 (283265) of the patients treated with SEROQUEL compared with 02 (2954) on placebo and about 04 (2527) on active control drugs Orthostatic hypotension dizziness and syncope may lead to falls

SEROQUEL should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease heart failure or conduction abnormalities) cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration hypovolemia and treatment with antihypertensive medications) The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [see Dosage and Administration (22)] If hypotension occurs during titration to the target dose a return to the previous dose in the titration schedule is appropriate

58 Falls Atypical antipsychotic drugs including SEROQUEL may cause somnolence postural hypotension motor and sensory instability which may lead to falls and consequently fractures or other injuries For patients with diseases conditions or medications that could exacerbate these effects complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy

59 Increases in Blood Pressure (Children and Adolescents) In placebo-controlled trials in children and adolescents with schizophrenia (6-week duration) or bipolar mania (3-week duration) the incidence of increases at any time in systolic blood pressure (ge20 mmHg) was 152 (51335) for SEROQUEL and 55 (9163) for placebo the incidence of increases at any time in diastolic blood pressure (ge10 mmHg) was 406 (136335) for SEROQUEL and 245 (40163) for placebo In the 26-week open-label clinical trial one child with a reported history of hypertension experienced a hypertensive crisis Blood pressure in children and adolescents should be measured at the beginning of and periodically during treatment

In a placebo-controlled SEROQUEL XR clinical trial (8 weeks duration) in children and adolescents (10-17 years of age) with bipolar depression in which efficacy was not established the incidence of increases at any time in systolic blood pressure (ge20 mmHg) was 65 (692) for SEROQUEL XR and 60 (6100) for placebo the incidence of increases at any time in diastolic blood pressure (ge10 mmHg) was 467 (4392) for SEROQUEL XR and 360 (36100) for placebo

510 Leukopenia Neutropenia and Agranulocytosis In clinical trial and postmarketing experience events of leukopenianeutropenia have been reported temporally related to atypical antipsychotic agents including SEROQUEL Agranulocytosis has been reported

Agranulocytosis (defined as absolute neutrophil count lt500mm3) has been reported with quetiapine including fatal cases and cases in patients without pre-existing risk factors Neutropenia should be considered in patients presenting with infection particularly in the absence of obvious predisposing factor(s) or in patients with unexplained fever and should be managed as clinically appropriate

Possible risk factors for leukopenianeutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenianeutropenia Patients with a pre-existing low WBC or a history of drug induced leukopenianeutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue SEROQUEL at the first sign of a decline in WBC in absence of other causative factors

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur Patients with severe neutropenia (absolute neutrophil count lt1000mm3) should discontinue SEROQUEL and have their WBC followed until recovery

511 Cataracts The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [see Nonclinical Toxicology (132)] Lens changes have also been observed in adults children and adolescents during longshyterm SEROQUEL treatment but a causal relationship to SEROQUEL use has not been established Nevertheless the possibility of lenticular changes cannot be excluded at this time Therefore examination of the lens by methods adequate to detect cataract formation such as slit lamp exam or other appropriately sensitive methods is recommended at initiation of treatment or shortly thereafter and at 6-month intervals during chronic treatment

512 QT Prolongation In clinical trials quetiapine was not associated with a persistent increase in QT intervals However the QT effect was not systematically evaluated in a thorough QT study In post marketing experience there were cases reported of QT prolongation in patients who overdosed on quetiapine [see Overdosage (101)] in patients with concomitant illness and in patients taking medicines known to cause electrolyte imbalance or increase QT interval [see Drug Interactions (71)]

The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (eg quinidine procainamide) or Class III antiarrythmics (eg amiodarone sotalol) antipsychotic medications (eg ziprasidone chlorpromazine thioridazine) antibiotics (eg gatifloxacin moxifloxacin) or any other class of medications known to prolong the QTc interval (eg pentamidine levomethadyl acetate methadone)

Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes andor sudden death including (1) a history of cardiac arrhythmias such as bradycardia (2) hypokalemia or hypomagnesemia (3) concomitant use of other drugs that prolong the QTc interval and (4) presence of congenital prolongation of the QT interval

Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (eg cardiovascular disease family history of QT prolongation the elderly congestive heart failure and heart hypertrophy)

513 Seizures During clinical trials seizures occurred in 05 (203490) of patients treated with SEROQUEL compared to 02 (2954) on placebo and 07 (4527) on active control drugs As with other antipsychotics SEROQUEL should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold eg Alzheimerrsquos dementia Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older

514 Hypothyroidism Adults Clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels The reduction in total and free thyroxine (T4) of approximately 20 at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy In nearly all cases cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4 irrespective of the duration of treatment The mechanism by which quetiapine effects the thyroid axis is unclear If there is an effect on the hypothalamic-pituitary axis measurement of TSH alone may not accurately reflect a patientrsquos thyroid status Therefore both TSH and free T4 in addition to clinical assessment should be measured at baseline and at follow-up

In the mania adjunct studies where SEROQUEL was added to lithium or divalproex 12 (24196) of SEROQUEL treated patients compared to 7 (15203) of placebo-treated patients had elevated TSH levels Of the SEROQUEL treated patients with elevated TSH levels 3 had simultaneous low free T4 levels (free T4 lt08 LLN)

About 07 (263489) of SEROQUEL patients did experience TSH increases in monotherapy studies Some patients with TSH increases needed replacement thyroid treatment

In all quetiapine trials the incidence of shifts in thyroid hormones and TSH were1 decrease in free T4 (lt08 LLN) 20 (35717513) decrease in total T4 (lt08LLN) 40 (751861) decrease in free T3 (lt08 LLN) 04 (5313766) decrease in total T3 (lt08LLN) 20 (261312) and increase in TSH (gt5mIUL) 49 (95619412) In eight patients where TBG was measured levels of TBG were unchanged

Table 8 shows the incidence of these shifts in short-term placebo-controlled clinical trials

Table 8 Incidence of Shifts in Thyroid Hormone Levels and TSH in Short-Term Placebo-Controlled Clinical Trials12

Total T4 Free T4 Total T3 Free T3 TSH Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo

34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)

1 Based on shifts from normal baseline to potentially clinically important value at any time post-baseline Shifts in total T4 free T4 total T3 and free T3 are defined as lt08 x LLN (pmolL) and shift in TSH is gt5 mlUL at any time


In short-term placebo-controlled monotherapy trials the incidence of reciprocal shifts in T3 and TSH was 00 for both quetiapine (14800) and placebo (02190) and for T4 and TSH the shifts were 01 (76154) for quetiapine versus 00 (13007) for placebo

Children and Adolescents In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6-week duration) or bipolar mania (3-week duration) the incidence of shifts for thyroid function values at any time for SEROQUEL treated patients and placebo-treated patients for elevated TSH was 29 (8280) vs 07 (1138) respectively and for decreased total thyroxine was 28 (8289) vs 0 (0145) respectively Of the SEROQUEL treated patients with elevated TSH levels 1 had simultaneous low free T4 level at end of treatment

515 Hyperprolactinemia Adults During clinical trials with quetiapine the incidence of shifts in prolactin levels to a clinically significant value occurred in 36 (1584416) of patients treated with quetiapine compared to 26 (511968) on placebo

1 Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline Shifts in total T4 free T4 total T3 and free T3 are defined as lt08 x LLN (pmolL) and shift in TSH is gt 5 mlUL at any time

Children and Adolescents In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3-week duration) or schizophrenia (6-week duration) the incidence of shifts in prolactin levels to a value (gt20 microgL males gt26 microgL females at any time) was 134 (18134) for SEROQUEL compared to 4 (375) for placebo in males and 87 (9104) for SEROQUEL compared to 0 (039) for placebo in females

Like other drugs that antagonize dopamine D2 receptors SEROQUEL elevates prolactin levels in some patients and the elevation may persist during chronic administration Hyperprolactinemia regardless of etiology may suppress hypothalamic GnRH resulting in reduced pituitary gonadotrophin secretion This in turn may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients Galactorrhea amenorrhea gynecomastia and impotence have been reported in patients receiving prolactin-elevating compounds Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer As is common with compounds which increase prolactin release mammary gland and pancreatic islet cell neoplasia (mammary adenocarcinomas pituitary and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans but the available evidence is too limited to be conclusive [see Nonclinical Toxicology (131)]

516 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse event reported in patients treated with SEROQUEL especially during the 3-5 day period of initial dose-titration In schizophrenia trials somnolence was reported in 18 (89510) of patients on SEROQUEL compared to 11 (22206) of placebo patients In acute bipolar mania trials using SEROQUEL as monotherapy somnolence was reported in 16 (34209) of patients on SEROQUEL compared to 4 of placebo patients In acute bipolar mania trials using SEROQUEL as adjunct therapy somnolence was reported in 34 (66196) of patients on SEROQUEL compared to 9 (19203) of placebo patients In bipolar depression trials somnolence was reported in 57 (398698) of patients on SEROQUEL compared to 15 (51347) of placebo patients Since SEROQUEL has the potential to impair judgment thinking or motor skills patients should be cautioned about performing activities requiring mental alertness such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that SEROQUEL therapy does not affect them adversely Somnolence may lead to falls

517 Body Temperature Regulation Although not reported with SEROQUEL disruption of the bodys ability to reduce core body temperature has been attributed to antipsychotic agents Appropriate care is advised when prescribing SEROQUEL for patients who will be experiencing conditions which may contribute to an elevation in core body temperature eg exercising strenuously exposure to extreme heat receiving concomitant medication with anticholinergic activity or being subject to dehydration

518 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients in particular those with advanced Alzheimers dementia SEROQUEL and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia

519 Discontinuation Syndrome Acute withdrawal symptoms such as insomnia nausea and vomiting have been described after abrupt cessation of atypical antipsychotic drugs including SEROQUEL In short-term placebo-controlled monotherapy clinical trials with SEROQUEL XR that included a discontinuation phase which evaluated discontinuation symptoms the aggregated

incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 121 (2411993) for SEROQUEL XR and 67 (711065) for placebo The incidence of the individual adverse reactions (ie insomnia nausea headache diarrhea vomiting dizziness and irritability) did not exceed 53 in any treatment group and usually resolved after 1 week post-discontinuation Gradual withdrawal is advised [see Use in Specific Populations (81)]

520 Anticholinergic (antimuscarinic) Effects Norquetiapine an active metabolite of quetiapine has moderate to strong affinity for several muscarinic receptor subtypes This contributes to anticholinergic adverse reactions when SEROQUEL is used at therapeutic doses taken concomitantly with other anticholinergic medications or taken in overdose SEROQUEL should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Overdosage (101) and Clinical Pharmacology (121)]

Constipation was a commonly reported adverse event in patients treated with quetiapine and represents a risk factor for intestinal obstruction Intestinal obstruction has been reported with quetiapine including fatal reports in patients who were receiving multiple concomitant medications that decrease intestinal motility

SEROQUEL should be used with caution in patients with a current diagnosis or prior history of urinary retention clinically significant prostatic hypertrophy constipation or increased intraocular pressure

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling

bull Increased mortality in elderly patients with dementia-related psychosis [see Warnings and Precautions (51)] bull Suicidal thoughts and behaviors in adolescents and young adults [see Warnings and Precautions (52)] bull Cerebrovascular adverse reactions including stroke in elderly patients with dementia-related psychosis [see Warnings

and Precautions (53)] bull Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (54)] bull Metabolic changes (hyperglycemia dyslipidemia weight gain) [see Warnings and Precautions (55)] bull Tardive dyskinesia [see Warnings and Precautions (56)] bull Hypotension [see Warnings and Precautions (57)] bull Falls [see Warnings and Precautions (58)] bull Increases in blood pressure (children and adolescents) [see Warnings and Precautions (59)] bull Leukopenia neutropenia and agranulocytosis [see Warnings and Precautions (510)] bull Cataracts [see Warnings and Precautions (511)] bull QT Prolongation [see Warnings and Precautions (512)] bull Seizures [see Warnings and Precautions (513)] bull Hypothyroidism [see Warnings and Precautions (514)] bull Hyperprolactinemia [see Warnings and Precautions (515)] bull Potential for cognitive and motor impairment [see Warnings and Precautions (516)] bull Body temperature regulation [see Warnings and Precautions (517)] bull Dysphagia [see Warnings and Precautions (518)] bull Discontinuation Syndrome [see Warnings and Precautions (519)] bull Anticholinergic (antimuscarinic) Effects [see Warnings and Precautions (520)]

61 Clinical Study Experience Because clinical studies are conducted under widely varying conditions adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice

Adults The information below is derived from a clinical trial database for SEROQUEL consisting of over 4300 patients This database includes 698 patients exposed to SEROQUEL for the treatment of bipolar depression 405 patients exposed to SEROQUEL for the treatment of acute bipolar mania (monotherapy and adjunct therapy) 646 patients exposed to SEROQUEL for the maintenance treatment of bipolar I disorder as adjunct therapy and approximately 2600 patients andor normal subjects exposed to 1 or more doses of SEROQUEL for the treatment of schizophrenia

Of these approximately 4300 subjects approximately 4000 (2300 in schizophrenia 405 in acute bipolar mania 698 in bipolar depression and 646 for the maintenance treatment of bipolar I disorder) were patients who participated in multiple dose effectiveness trials and their experience corresponded to approximately 2400 patient-years The conditions and duration of treatment with SEROQUEL varied greatly and included (in overlapping categories) open-label and double-blind phases of studies inpatients and outpatients fixed-dose and dose-titration studies and short-term or longer-term exposure Adverse reactions were assessed by collecting adverse reactions results of physical examinations vital signs weights laboratory analyses ECGs and results of ophthalmologic examinations

The stated frequencies of adverse reactions represent the proportion of individuals who experienced at least once an adverse reaction of the type listed

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term Placebo-Controlled Trials

Schizophrenia Overall there was little difference in the incidence of discontinuation due to adverse reactions (4 for SEROQUEL vs 3 for placebo) in a pool of controlled trials However discontinuations due to somnolence (08 SEROQUEL vs 0 placebo) and hypotension (04 SEROQUEL vs 0 placebo) were considered to be drug related [see Warnings and Precautions (57 and 519)]

Bipolar Disorder

Mania Overall discontinuations due to adverse reactions were 57 for SEROQUEL vs 51 for placebo in monotherapy and 36 for SEROQUEL vs 59 for placebo in adjunct therapy Depression Overall discontinuations due to adverse reactions were 123 for SEROQUEL 300 mg vs 190 for SEROQUEL 600 mg and 52 for placebo

Commonly Observed Adverse Reactions in Short-Term Placebo-Controlled Trials

In the acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) trials the most commonly observed adverse reactions associated with the use of SEROQUEL monotherapy (incidence of 5 or greater) and observed at a rate on SEROQUEL at least twice that of placebo were somnolence (18) dizziness (11) dry mouth (9) constipation (8) ALT increased (5) weight gain (5) and dyspepsia (5)

Adverse Reactions Occurring at an Incidence of 2 or More Among SEROQUEL Treated Patients in Short-Term Placebo-Controlled Trials

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials Similarly the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments uses and investigators The cited figures however do provide the

prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence in the population studied

Table 9 enumerates the incidence rounded to the nearest percent of adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) in 2 or more of patients treated with SEROQUEL (doses ranging from 75 to 800 mgday) where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients

Table 9 Adverse Reaction Incidence in 3- to 12-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia and Bipolar Mania (Monotherapy)

Preferred Term SEROQUEL (n=719)

PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1

Postural Hypotension 4 1

Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1

In the acute adjunct therapy of bipolar mania (up to 3 weeks) studies the most commonly observed adverse reactions associated with the use of SEROQUEL (incidence of 5 or greater) and observed at a rate on SEROQUEL at least twice that of placebo were somnolence (34) dry mouth (19) asthenia (10) constipation (10) abdominal pain (7) postural hypotension (7) pharyngitis (6) and weight gain (6)

Table 10 enumerates the incidence rounded to the nearest percent of adverse reactions that occurred during therapy (up to 3 weeks) of acute mania in 2 or more of patients treated with SEROQUEL (doses ranging from 100 to 800 mgday) used as adjunct therapy to lithium and divalproex where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients

Table 10 Adverse Reaction Incidence in 3-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Mania (Adjunct Therapy)


PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2

Peripheral Edema 4 2

Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1

Hormone Level Altered

3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1

Increased Appetite 2 1

Hypothyroidism 2 1

Incoordination 2 1

Thinking Abnormal 2 0

Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1

Urinary Tract Infection

2 1

In bipolar depression studies (up to 8 weeks) the most commonly observed adverse reactions associated with the use of SEROQUEL (incidence of 5 or greater) and observed at a rate on SEROQUEL at least twice that of placebo were somnolence (57) dry mouth (44) dizziness (18) constipation (10) and lethargy (5)

Table 11 enumerates the incidence rounded to the nearest percent of adverse reactions that occurred during therapy (up to 8 weeks) of bipolar depression in 2 or more of patients treated with SEROQUEL (doses of 300 and 600 mgday) where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients

Table 11 Adverse Reaction Incidence in 8-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Depression


PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2

Nasal Congestion 5 3

Orthostatic Hypotension 4 3

Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2

Weight increased 4 1

Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1

Extrapyramidal Disorder 3 1

Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0

Sinus Congestion 2 1

Abnormal Dreams 2 1

Tremor 2 1

Gastroesophageal Reflux Disease

2 1

Pain in Extremity 2 1

Asthenia 2 1

Balance Disorder 2 1

Hypoesthesia 2 1

Dysphagia 2 0

Restless Legs Syndrome 2 0 1 Somnolence combines adverse reaction terms somnolence and sedation

Explorations for interactions on the basis of gender age and race did not reveal any clinically meaningful differences in the adverse reaction occurrence on the basis of these demographic factors

Dose Dependency of Adverse Reactions in Short-Term Placebo-Controlled Trials

Dose-related Adverse Reactions Spontaneously elicited adverse reaction data from a study of schizophrenia comparing five fixed doses of SEROQUEL (75 mg 150 mg 300 mg 600 mg and 750 mgday) to placebo were explored for dose-relatedness of adverse reactions Logistic regression analyses revealed a positive dose response (plt005) for the following adverse reactions dyspepsia abdominal pain and weight gain

Adverse Reactions in clinical trials with quetiapine and not listed elsewhere in the label

The following adverse reactions have also been reported with quetiapine nightmares hypersensitivity and elevations in serum creatine phosphokinase (not associated with NMS) galactorrhea bradycardia (which may occur at or near initiation of treatment and be associated with hypotension andor syncope) decreased platelets somnambulism (and other related events) elevations in gamma-GT levels hypothermia dyspnea eosinophilia urinary retention intestinal obstruction and priapism

Extrapyramidal Symptoms (EPS) Dystonia Class Effect Symptoms of dystonia prolonged abnormal contractions of muscle groups may occur in susceptible individuals during the first few days of treatment Dystonic symptoms include spasm of the neck muscles sometimes progressing to tightness of the throat swallowing difficulty difficulty breathing andor protrusion of the tongue While these symptoms can occur at low doses they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs An elevated risk of acute dystonia is observed in males and younger age groups

Four methods were used to measure EPS (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia (2) Barnes Akathisia Rating Scale (BARS) Global Assessment Score (3) incidence of spontaneous complaints of EPS (akathisia akinesia cogwheel rigidity extrapyramidal syndrome hypertonia hypokinesia neck rigidity and tremor) and (4) use of anticholinergic medications to treat EPS

Adults Data from one 6-week clinical trial of schizophrenia comparing five fixed doses of SEROQUEL (75 150 300 600 750 mgday) provided evidence for the lack of extrapyramidal symptoms (EPS) and dose-relatedness for EPS associated with SEROQUEL treatment Three methods were used to measure EPS (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia (2) incidence of spontaneous complaints of EPS (akathisia akinesia cogwheel rigidity extrapyramidal syndrome hypertonia hypokinesia neck rigidity and tremor) and (3) use of anticholinergic medications to EPS

In Table 12 dystonic event included nuchal rigidity hypertonia dystonia muscle rigidity oculogyration parkinsonism included cogwheel rigidity tremor drooling hypokinesia akathisia included akathisia psychomotor agitation dyskinetic event included tardive dyskinesia dyskinesia choreoathetosis and other extrapyramidal event included restlessness extrapyramidal disorder movement disorder

Table 12 Adverse Reactions Associated with EPS in a Short-Term Placebo-Controlled Multiple Fixed-Dose Phase III Schizophrenia Trial (6 weeks duration)

Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday

(N=54) Placebo (N=51)

n n n n n n Dystonic event 2 38 2 42 0 00 2 39 3 56 4 78

Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00

Other extrapyramidal event

2 38 0 00 3 58 3 59 1 19 4 78

Parkinsonism incidence rates as measured by the Simpson-Angus total score for placebo and the five fixed doses (75 150 300 600 750 mgday) were -06 -10 -12 -16 -18 and -18 The rate of anticholinergic medication use to treat EPS for placebo and the five fixed doses was 14 11 10 8 12 and 11

In six additional placebo-controlled clinical trials (3 in acute mania and 3 in schizophrenia) using variable doses of SEROQUEL there were no differences between the SEROQUEL and placebo treatment groups in the incidence of EPS as assessed by Simpson-Angus total scores spontaneous complaints of EPS and the use of concomitant anticholinergic medications to treat EPS

In two placebo-controlled clinical trials for the treatment of bipolar depression using 300 mg and 600 mg of SEROQUEL the incidence of adverse reactions potentially related to EPS was 12 in both dose groups and 6 in the placebo group In these studies the incidence of the individual adverse reactions (akathisia extrapyramidal disorder tremor dyskinesia dystonia restlessness muscle contractions involuntary psychomotor hyperactivity and muscle rigidity) were generally low and did not exceed 4 in any treatment group

The 3 treatment groups were similar in mean change in SAS total score and BARS Global Assessment score at the end of treatment The use of concomitant anticholinergic medications was infrequent and similar across the three treatment groups

Children and Adolescents

The information below is derived from a clinical trial database for SEROQUEL consisting of over 1000 pediatric patients This database includes 677 patients exposed to SEROQUEL for the treatment of schizophrenia and 393 children and adolescents (10-17 years old) exposed to SEROQUEL for the treatment of acute bipolar mania


Schizophrenia The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 82 and 27 respectively The adverse event leading to discontinuation in 1 or more of patients on SEROQUEL and at a greater incidence than placebo was somnolence (27 and 0 for placebo)

Bipolar I Mania The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 114 and 44 respectively The adverse reactions leading to discontinuation in 2 or more of patients on SEROQUEL and at a greater incidence than placebo were somnolence (41 vs 11) and fatigue (21 vs 0)


In therapy for schizophrenia (up to 6 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5 or greater and quetiapine incidence at least twice that for placebo) were somnolence (34) dizziness (12) dry mouth (7) tachycardia (7)

In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5 or greater and quetiapine incidence at least twice that for placebo) were somnolence (53) dizziness (18) fatigue (11) increased appetite (9) nausea (8) vomiting (8) tachycardia (7) dry mouth (7) and weight increased (6)

In an acute (8-week) SEROQUEL XR trial in children and adolescents (10-17 years of age) with bipolar depression in which efficacy was not established the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5 or greater and at least twice that for placebo) were dizziness 7 diarrhea 5 fatigue 5 and nausea 5

Adverse Reactions Occurring at an Incidence of ge 2 among SEROQUEL Treated Patients in Short-Term Placebo-Controlled Trials

Schizophrenia (Adolescents 13-17 years old) The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mgday

Table 13 enumerates the incidence rounded to the nearest percent of adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 2 or more of patients treated with SEROQUEL (doses of 400 or 800 mgday) where the incidence in patients treated with SEROQUEL was at least twice the incidence in placebo-treated patients

Adverse reactions that were potentially dose-related with higher frequency in the 800 mg group compared to the 400 mg group included dizziness (8 vs 15) dry mouth (4 vs 10) and tachycardia (6 vs 11)

Table 13 Adverse Reaction Incidence in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients

Preferred Term SEROQUEL 400 mg (n=73)

SEROQUEL 800 mg (n=74)

Placebo (n=75)

Somnolence1 33 35 11

Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0

Abdominal Pain 3 1 0

Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1

Muscle Rigidity 3 0 0 1 Somnolence combines adverse reaction terms somnolence and sedation 2 Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia

Bipolar I Mania (Children and Adolescents 10-17 years old)

The following findings were based on a 3-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 600 mgday

Commonly Observed Adverse Reactions


Table 14 enumerates the incidence rounded to the nearest percent of adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 2 or more of patients treated with SEROQUEL (doses of 400 or 600 mgday) where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients

Adverse reactions that were potentially dose-related with higher frequency in the 600 mg group compared to the 400 mg group included somnolence (50 vs 57) nausea (6 vs 10) and tachycardia (6 vs 9)

Table 14 Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of BipolarMania in Children and Adolescent Patients



Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4

Increased Appetite 10 9 1

Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3

Nasal Congestion 3 6 2

Weight Increased 6 6 0

Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0

Musculoskeletal Stiffness 1 3 1

Accidental Overdose 0 2 0

Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0

Stomach Discomfort 4 2 1

Syncope 2 2 0

Vision Blurred 3 2 0

Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0

Sinus Congestion 3 0 0

Thirst 2 0 0 1 Somnolence combines adverse reactions terms somnolence and sedation 2 Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia

Extrapyramidal Symptoms In a short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration) the aggregated incidence of extrapyramidal symptoms was 129 (19147) for SEROQUEL and 53 (475) for placebo though the incidence of the individual adverse reactions (akathisia tremor extrapyramidal disorder hypokinesia restlessness psychomotor hyperactivity muscle rigidity dyskinesia) did not exceed 41 in any treatment group In a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration) the aggregated incidence of extrapyramidal symptoms was 36 (7193) or SEROQUEL and 11 (190) for placebo

Table 15 presents a listing of patients with adverse reactions potentially associated with extrapyramidal symptoms in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration)

In Tables 15ndash16 dystonic event included nuchal rigidity hypertonia and muscle rigidity parkinsonism included cogwheel rigidity and tremor akathisia included akathisia only dyskinetic event included tardive dyskinesia dyskinesia and choreoathetosis and other extrapyramidal event included restlessness and extrapyramidal disorder

Table 15 Adverse Reactions Associated with Extrapyramidal Symptoms in the Placebo-controlled Trialin Adolescent Patients with Schizophrenia (6-week duration)

Preferred Term SEROQUEL 400 mgday

(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL


n n n n Dystonic event 2 27 0 00 2 14 0 00

Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40

Dyskinetic event 2 27 0 00 2 14 0 00

Other Extrapyramidal Event

2 27 2 27 4 27 0 00

Table 16 presents a listing of patients with adverse reactions associated with extrapyramidal symptoms in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration)

Table 16 Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Trialin Children and Adolescent Patients with Bipolar I Mania (3-week duration)

Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL


n n n n Parkinsonism 2 21 1 10 3 16 1 11

Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00

1 There were no adverse reactions with the preferred term of dystonic or dyskinetic events

Laboratory ECG and vital sign changes observed in clinical studies Laboratory Changes

Neutrophil Counts Adults In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine and 1515 on placebo the incidence of at least one occurrence of neutrophil count lt10 x 109L among patients with a normal baseline neutrophil count and at least one available follow up laboratory measurement was 03 (102967) in patients treated with quetiapine compared to 01 (21349) in patients treated with placebo [see Warnings and Precautions (510)]

Transaminase Elevations Adults Asymptomatic transient and reversible elevations in serum transaminases (primarily ALT) have been reported In schizophrenia trials in adults the proportions of patients with transaminase elevations of gt3 times the upper limits of the normal reference range in a pool of 3- to 6-week placebo-controlled trials were approximately 6 (29483) for SEROQUEL compared to 1 (3194) for placebo In acute bipolar mania trials in adults the proportions of patients with transaminase elevations of gt3 times the upper limits of the normal reference range in a pool of 3- to 12-week placebo-controlled trials were approximately 1 for both SEROQUEL (3560) and placebo (3294) These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with SEROQUEL In bipolar depression trials the proportions of patients with transaminase elevations of gt3 times the upper limits of the normal reference range in two 8-week placebo-controlled trials was 1 (5698) for SEROQUEL and 2 (6347) for placebo

Decreased Hemoglobin Adults In short-term placebo-controlled trials decreases in hemoglobin to le13 gdL males le12 gdL females on at least one occasion occurred in 83 (5947155) of quetiapine-treated patients compared to 62 (2193536) of patients treated

with placebo In a database of controlled and uncontrolled clinical trials decreases in hemoglobin to le13 gdL males le12 gdL females on at least one occasion occurred in 11 (227720729) of quetiapine-treated patients

Interference with Urine Drug Screens There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine Caution should be exercised in the interpretation of positive urine drug screen results for these drugs and confirmation by alternative analytical technique (eg chromatographic methods) should be considered

ECG Changes Adults Between-group comparisons for pooled placebo-controlled trials revealed no statistically significant SEROQUELplacebo differences in the proportions of patients experiencing potentially important changes in ECG parameters including QT QTc and PR intervals However the proportions of patients meeting the criteria for tachycardia were compared in four 3- to 6-week placebo-controlled clinical trials for the treatment of schizophrenia revealing a 1 (4399) incidence for SEROQUEL compared to 06 (1156) incidence for placebo In acute (monotherapy) bipolar mania trials the proportions of patients meeting the criteria for tachycardia was 05 (1192) for SEROQUEL compared to 0 (0178) incidence for placebo In acute bipolar mania (adjunct) trials the proportions of patients meeting the same criteria was 06 (1166) for SEROQUEL compared to 0 (0171) incidence for placebo In bipolar depression trials no patients had heart rate increases to gt120 beats per minute SEROQUEL use was associated with a mean increase in heart rate assessed by ECG of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients This slight tendency to tachycardia in adults may be related to SEROQUELs potential for inducing orthostatic changes [see Warnings and Precautions (57)]

Children and Adolescents In the acute (6-week) schizophrenia trial in adolescents increases in heart rate (gt110 bpm) occurred in 52 (373) of patients receiving SEROQUEL 400 mg and 85 (574) of patients receiving SEROQUEL 800 mg compared to 0 (075) of patients receiving placebo Mean increases in heart rate were 38 bpm and 112 bpm for SEROQUEL 400 mg and 800 mg groups respectively compared to a decrease of 33 bpm in the placebo group [see Warnings and Precautions (57)]

In the acute (3-week) bipolar mania trial in children and adolescents increases in heart rate (gt110 bpm) occurred in 11 (189) of patients receiving SEROQUEL 400 mg and 47 (485) of patients receiving SEROQUEL 600 mg compared to 0 (098) of patients receiving placebo Mean increases in heart rate were 128 bpm and 134 bpm for SEROQUEL 400 mg and 600 mg groups respectively compared to a decrease of 17 bpm in the placebo group [see Warnings and Precautions (57)]

In an acute (8-week) SEROQUEL XR trial in children and adolescents (10-17 years of age) with bipolar depression in which efficacy was not established increases in heart rate (gt110 bpm 10-12 years and 13-17 years) occurred in 0 of patients receiving SEROQUEL XR and 12 of patients receiving placebo Mean increases in heart rate were 34 bpm for SEROQUEL XR compared to 03 bpm in the placebo group [see Warnings and Precautions (57)]

62 Postmarketing Experience The following adverse reactions were identified during post approval of SEROQUEL Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure

Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include anaphylactic reaction cardiomyopathy drug reaction with eosinophilia and systemic symptoms (DRESS) hyponatremia myocarditis nocturnal enuresis pancreatitis retrograde amnesia rhabdomyolysis syndrome of inappropriate antidiuretic hormone secretion (SIADH) Stevens-Johnson syndrome (SJS) toxic epidermal necrolysis (TEN) decreased platelet count serious liver reactions (including hepatitis liver necrosis and hepatic failure) agranulocytosis intestinal

obstruction ileus colon ischemia urinary retention sleep apnea and acute generalized exanthematous pustulosis (AGEP)

7 DRUG INTERACTIONS

71 Effect of Other Drugs on Quetiapine The risks of using SEROQUEL in combination with other drugs have not been extensively evaluated in systematic studies Given the primary CNS effects of SEROQUEL caution should be used when it is taken in combination with other centrally acting drugs SEROQUEL potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders and alcoholic beverages should be limited while taking quetiapine

Quetiapine exposure is increased by the prototype CYP3A4 inhibitors (eg ketoconazole itraconazole indinavir ritonavir nefazodone etc) and decreased by the prototype CYP3A4 inducers (eg phenytoin carbamazepine rifampin avasimibe St Johnrsquos wort etc) Dose adjustment of quetiapine will be necessary if it is co-administered with potent CYP3A4 inducers or inhibitors

CYP3A4 inhibitors Coadministration of ketoconazole a potent inhibitor of cytochrome CYP3A4 resulted in significant increase in quetiapine exposure The dose of SEROQUEL should be reduced to one sixth of the original dose if co-administered with a strong CYP3A4 inhibitor [see Dosage and Administration (25) and Clinical Pharmacology (123)]

CYP3A4 inducers Coadministration of quetiapine and phenytoin a CYP3A4 inducer increased the mean oral clearance of quetiapine by 5shyfold Increased doses of SEROQUEL up to 5 fold may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin or other known potent CYP3A4 inducers [see Dosage and Administration (26) and Clinical Pharmacology (123)] When the CYP3A4 inducer is discontinued the dose of SEROQUEL should be reduced to the original level within 7-14 days [see Dosage and Administration (26)]

The potential effects of several concomitant medications on quetiapine pharmacokinetics were studied [see Clinical Pharmacology (123)]

72 Effect of Quetiapine on Other Drugs Because of its potential for inducing hypotension SEROQUEL may enhance the effects of certain antihypertensive agents

SEROQUEL may antagonize the effects of levodopa and dopamine agonists

There are no clinically relevant pharmacokinetic interactions of Seroquel on other drugs based on the CYP pathway Seroquel and its metabolites are non-inhibitors of major metabolizing CYPrsquos (1A2 2C9 2C19 2D6 and 3A4)

8 USE IN SPECIFIC POPULATIONS

81 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics including SEROQUEL during pregnancy Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at httpwomensmentalhealthorgclinical-and-research-programspregnancyregistry

Risk Summary

Neonates exposed to antipsychotic drugs (including SEROQUEL) during the third trimester are at risk for extrapyramidal andor withdrawal symptoms following delivery (see Clinical Considerations) Overall available data from published epidemiologic studies of pregnant women exposed to quetiapine have not established a drug-associated risk of major birth defects miscarriage or adverse maternal or fetal outcomes (see Data) There are risks to the mother associated with untreated schizophrenia bipolar I or major depressive disorder and with exposure to antipsychotics including SEROQUEL during pregnancy (see Clinical Considerations)

In animal studies embryo-fetal toxicity occurred including delays in skeletal ossification at approximately 1 and 2 times the maximum recommended human dose (MRHD) of 800 mgday in both rats and rabbits and an increased incidence of carpaltarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD In addition fetal weights were decreased in both species Maternal toxicity (observed as decreased body weights andor death) occurred at 2 times the MRHD in rats and approximately 1-2 times the MRHD in rabbits

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown All pregnancies have a background risk of birth defect loss or other adverse outcomes In the US general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 and 15 to 20 respectively

Clinical Considerations Disease-associated maternal andor fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder including increased risk of relapse hospitalization and suicide Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes including preterm birth It is not known if this is a direct result of the illness or other comorbid factors

A prospective longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum

Fetalneonatal adverse reactions Extrapyramidal andor withdrawal symptoms including agitation hypertonia hypotonia tremor somnolence respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs including SEROQUEL during the third trimester of pregnancy These symptoms varied in severity Monitor neonates for extrapyramidal andor withdrawal symptoms and manage symptoms appropriately Some neonates recovered within hours or days without specific treatment others required prolonged hospitalization

Data Human Data Published data from observational studies birth registries and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk of major birth defects

Animal Data When pregnant rats and rabbits were exposed to quetiapine during organogenesis there was no teratogenic effect in fetuses Doses were 25 50 and 200 mgkg in rats and 25 50 and 100 mgkg in rabbits which are approximately 03 06 and 2-times (rats) and 06 1 and 2-times (rabbits) the MRHD for schizophrenia of 800 mgday based on mgm2 body surface area However there was evidence of embryo-fetal toxicity including delays in skeletal ossification at approximately 1 and 2 times the MRHD of 800 mgday in both rats and rabbits and an increased incidence of carpaltarsal

flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD In addition fetal weights were decreased in both species Maternal toxicity (observed as decreased body weights andor death) occurred at 2 times the MRHD in rats and approximately 1-2 times the MRHD (all doses tested) in rabbits

In a peripostnatal reproductive study in rats no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 001 01 and 02 times the MRHD of 800 mgday based on mgm2 body surface area However in a preliminary peripostnatal study there were increases in fetal and pup death and decreases in mean litter weight at 3 times the MRHD

82 Lactation Risk Summary

Limited data from published literature report the presence of quetiapine in human breast milk at relative infant dose of lt1 of the maternal weight-adjusted dosage There are no consistent adverse events that have been reported in infants exposed to quetiapine through breast milk There is no information on the effects of quetiapine on milk production The developmental and health benefits of breastfeeding should be considered along with the motherrsquos clinical need for SEROQUEL and any potential adverse effects on the breastfed child from SEROQUEL or from the motherrsquos underlying condition

83 Females and Males of Reproductive Potential

Infertility Females

Based on the pharmacologic action of quetiapine (D2 antagonism) treatment with SEROQUEL may result in an increase in serum prolactin levels which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (515)]

84 Pediatric Use In general the adverse reactions observed in children and adolescents during the clinical trials were similar to those in the adult population with few exceptions Increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults Orthostatic hypotension occurred more frequently in adults (4-7) compared to children and adolescents (lt 1) [see Warnings and Precautions (57) and Adverse Reactions (61)]

Schizophrenia The efficacy and safety of SEROQUEL in the treatment of schizophrenia in adolescents aged 13-17 years were demonstrated in one 6-week double-blind placebo-controlled trial [see Indications and Usage (11) Dosage and Administration (22) Adverse Reactions (61) and Clinical Studies (141)]

Safety and effectiveness of SEROQUEL in pediatric patients less than 13 years of age with schizophrenia have not been established

Maintenance The safety and effectiveness of SEROQUEL in the maintenance treatment of bipolar disorder has not been established in pediatric patients less than 18 years of age The safety and effectiveness of SEROQUEL in the maintenance treatment of schizophrenia has not been established in any patient population including pediatric patients

Bipolar Mania The efficacy and safety of SEROQUEL in the treatment of mania in children and adolescents ages 10-17 years with bipolar I disorder was demonstrated in a 3-week double-blind placebo controlled multicenter trial [see Indications and Usage (12) Dosage and Administration (23) Adverse Reactions (61) and Clinical Studies (142)]

Safety and effectiveness of SEROQUEL in pediatric patients less than 10 years of age with bipolar mania have not been established

Bipolar Depression Safety and effectiveness of SEROQUEL in pediatric patients less than 18 years of age with bipolar depression have not been established A clinical trial with SEROQUEL XR was conducted in children and adolescents (10-17 years of age) with bipolar depression efficacy was not established

Some differences in the pharmacokinetics of quetiapine were noted between childrenadolescents (10-17 years of age) and adults When adjusted for weight the AUC and Cmax of quetiapine were 41 and 39 lower respectively in children and adolescents compared to adults The pharmacokinetics of the active metabolite norquetiapine were similar between childrenadolescents and adults after adjusting for weight [see Clinical Pharmacology (123)]

85 Geriatric Use Of the approximately 3700 patients in clinical studies with SEROQUEL 7 (232) were 65 years of age or over In general there was no indication of any different tolerability of SEROQUEL in the elderly compared to younger adults Nevertheless the presence of factors that might decrease pharmacokinetic clearance increase the pharmacodynamic response to SEROQUEL or cause poorer tolerance or orthostasis should lead to consideration of a lower starting dose slower titration and careful monitoring during the initial dosing period in the elderly The mean plasma clearance of SEROQUEL was reduced by 30 to 50 in elderly patients when compared to younger patients [see Clinical Pharmacology (123) and Dosage and Administration (23)]

86 Renal Impairment Clinical experience with SEROQUEL in patients with renal impairment is limited [see Clinical Pharmacology (123)]

87 Hepatic Impairment Since quetiapine is extensively metabolized by the liver higher plasma levels are expected in patients with hepatic impairment In this population a low starting dose of 25 mgday is recommended and the dose may be increased in increments of 25 mgday-50 mgday [see Dosage and Administration (24) and Clinical Pharmacology (123)]

9 DRUG ABUSE AND DEPENDENCE

91 Controlled Substance SEROQUEL is not a controlled substance

92 Abuse SEROQUEL has not been systematically studied in animals or humans for its potential for abuse tolerance or physical dependence While the clinical trials did not reveal any tendency for any drug-seeking behavior these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused diverted andor abused once marketed Consequently patients should be evaluated carefully for a history of drug abuse and such patients should be observed closely for signs of misuse or abuse of SEROQUEL eg development of tolerance increases in dose drug-seeking behavior

10 OVERDOSAGE

101 Human Experience In clinical trials survival has been reported in acute overdoses of up to 30 grams of quetiapine Most patients who overdosed experienced no adverse reactions or recovered fully from the reported reactions Death has been reported in a clinical trial following an overdose of 136 grams of quetiapine alone In general reported signs and symptoms were those

resulting from an exaggeration of the drugrsquos known pharmacological effects ie drowsiness sedation tachycardia hypotension and anticholinergic toxicity including coma and delirium Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose [see Warnings and Precautions (512)] One case involving an estimated overdose of 9600 mg was associated with hypokalemia and first-degree heart block In post-marketing experience there were cases reported of QT prolongation with overdose

102 Management of Overdosage Establish and maintain an airway and ensure adequate oxygenation and ventilation Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias

Appropriate supportive measures are the mainstay of management For the most up-to-date information on the management of Seroquel overdosage contact a certified Regional Poison Control Center (1-800-222-1222)

11 DESCRIPTION

SEROQUELreg (quetiapine) is an atypical antipsychotic belonging to a chemical class the dibenzothiazepine derivatives The chemical designation is 2-[2-(4-dibenzo [bf] [14]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (21) (salt) It is present in tablets as the fumarate salt All doses and tablet strengths are expressed as milligrams of base not as fumarate salt Its molecular formula is C42H50N6O4S2bullC4H4O4 and it has a molecular weight of 88311 (fumarate salt) The structural formula is

Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water

SEROQUEL is supplied for oral administration as 25 mg (round peach) 50 mg (round white) 100 mg (round yellow) 200 mg (round white) 300 mg (capsule-shaped white) and 400 mg (capsule-shaped yellow) tablets

Inactive ingredients are povidone dibasic dicalcium phosphate dihydrate microcrystalline cellulose sodium starch glycolate lactose monohydrate magnesium stearate hypromellose polyethylene glycol and titanium dioxide

The 25 mg tablets contain red ferric oxide and yellow ferric oxide and the 100 mg and 400 mg tablets contain only yellow ferric oxide

Each 25 mg tablet contains 2878 mg of quetiapine fumarate equivalent to 25 mg quetiapine Each 50 mg tablet contains 5756 mg of quetiapine fumarate equivalent to 50 mg quetiapine Each 100 mg tablet contains 11513 mg of quetiapine fumarate equivalent to 100 mg quetiapine Each 200 mg tablet contains 23026 mg of quetiapine fumarate equivalent to 200 mg quetiapine Each 300 mg tablet contains 34539 mg of quetiapine fumarate equivalent to 300 mg quetiapine Each 400 mg tablet contains 46051 mg of quetiapine fumarate equivalent to 400 mg quetiapine

12 CLINICAL PHARMACOLOGY

121 Mechanism of Action The mechanism of action of quetiapine in the listed indications is unclear However the efficacy of quetiapine in these indications could be mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism The active metabolite N-desalkyl quetiapine (norquetiapine) has similar activity at D2 but greater activity at 5HT2A

receptors than the parent drug (quetiapine)

122 Pharmacodynamics Quetiapine and its metabolite norquetiapine have affinity for multiple neurotransmitter receptors with norquetiapine binding with higher affinity than quetiapine in general The Ki values for quetiapine and norquetiapine at the dopamine D1 are 428998 nM at D2 626489nM at serotonin 5HT1A 1040191 nM at 5HT2A 3829 nM at histamine H1 4411 nM at muscarinic M1 1086383 nM and at adrenergic α1b 146464 nM and at α2 receptors 6171290 nM respectively Quetiapine and norquetiapine lack appreciable affinity to the benzodiazepine receptors

Effect on QT Interval In clinical trials quetiapine was not associated with a persistent increase in QT intervals However the QT effect was not systematically evaluated in a thorough QT study In post marketing experience there were cases reported of QT prolongation in patients who overdosed on quetiapine [see Overdosage (101)] in patients with concomitant illness and in patients taking medicines known to cause electrolyte imbalance or increase QT interval

123 Pharmacokinetics Adults Quetiapine activity is primarily due to the parent drug The multiple-dose pharmacokinetics of quetiapine are dose-proportional within the proposed clinical dose range and quetiapine accumulation is predictable upon multiple dosing Elimination of quetiapine is mainly via hepatic metabolism with a mean terminal half-life of about 6 hours within the proposed clinical dose range Steady-state concentrations are expected to be achieved within two days of dosing Quetiapine is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes

Children and Adolescents At steady state the pharmacokinetics of the parent compound in children and adolescents (10-17 years of age) were similar to adults However when adjusted for dose and weight AUC and Cmax of the parent compound were 41 and 39 lower respectively in children and adolescents than in adults For the active metabolite norquetiapine AUC and Cmax were 45 and 31 higher respectively in children and adolescents than in adults When adjusted for dose and weight the pharmacokinetics of the metabolite norquetiapine was similar between children and adolescents and adults [see Use in Specific Populations (84)]

Absorption Quetiapine is rapidly absorbed after oral administration reaching peak plasma concentrations in 15 hours The tablet formulation is 100 bioavailable relative to solution The bioavailability of quetiapine is marginally affected by administration with food with Cmax and AUC values increased by 25 and 15 respectively

Distribution

Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10plusmn4 Lkg It is 83 bound to plasma proteins at therapeutic concentrations In vitro quetiapine did not affect the binding of warfarin or diazepam to human serum albumin In turn neither warfarin nor diazepam altered the binding of quetiapine

Metabolism and Elimination Following a single oral dose of 14C-quetiapine less than 1 of the administered dose was excreted as unchanged drug indicating that quetiapine is highly metabolized Approximately 73 and 20 of the dose was recovered in the urine and feces respectively

Quetiapine is extensively metabolized by the liver The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite both metabolites are pharmacologically inactive In vitro studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major but inactive sulfoxide metabolite and in the metabolism of its active metabolite N-desalkyl quetiapine

Age Oral clearance of quetiapine was reduced by 40 in elderly patients (ge 65 years n=9) compared to young patients (n=12) and dosing adjustment may be necessary [see Dosage and Administration (23)]

Gender There is no gender effect on the pharmacokinetics of quetiapine

Race There is no race effect on the pharmacokinetics of quetiapine

Smoking Smoking has no effect on the oral clearance of quetiapine

Renal Insufficiency Patients with severe renal impairment (Clcr=10-30 mLmin173 m2 n=8) had a 25 lower mean oral clearance than normal subjects (Clcr gt 80 mLmin173 m2 n=8) but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose Dosage adjustment is therefore not needed in these patients [see Use in Specific Populations (86)]

Hepatic Insufficiency Hepatically impaired patients (n=8) had a 30 lower mean oral clearance of quetiapine than normal subjects In two of the 8 hepatically impaired patients AUC and Cmax were 3 times higher than those observed typically in healthy subjects Since quetiapine is extensively metabolized by the liver higher plasma levels are expected in the hepatically impaired population and dosage adjustment may be needed [see Dosage and Administration (24) and Use in Specific Populations (87)]

Drug-Drug Interaction Studies The in vivo assessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in Table 17 [see Dosage and Administration (25 and 26) and Drug Interactions (71)]

Table 17 The Effect of Other Drugs on the Pharmacokinetics of Quetiapine

Coadministered Drug

Dose Schedules Effect on Quetiapine Pharmacokinetics Coadministered

Drug Quetiapine

Phenytoin 100 mg three times daily

250 mg three times daily

5-fold increase in oral clearance

Divalproex 500 mg twice daily

150 mg twice daily

17 increase mean max plasma concentration at steady state No effect on absorption or mean oral clearance

Thioridazine 200 mg twice daily

300 mg twice daily

65 increase in oral clearance

Cimetidine 400 mg three times daily for 4 days


20 decrease in mean oral clearance

Ketoconazole (potent CYP 3A4 inhibitor)

200 mg once daily for 4 days

25 mg single dose

84 decrease in oral clearance resulting in a 62-fold increase in AUC of quetiapine

Fluoxetine 60 mg once daily

300 mg twice daily

No change in steady state PK

Imipramine 75 mg twice daily

300 mg twice daily


Haloperidol 75 mg twice daily

300 mg twice daily


Risperidone 3 mg twice daily

300 mg twice daily


In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes CYP 1A2 2C9 2C19 2D6 and 3A4 Quetiapine at doses of 750 mgday did not affect the single dose pharmacokinetics of antipyrine lithium or lorazepam (Table 18) [see Drug Interactions (72)]

Table 18 The Effect of Quetiapine on the Pharmacokinetics of Other Drugs

Coadministered drug

Dose schedules Effect on other drugs pharmacokinetics Coadministered

drug Quetiapine

Lorazepam 2 mg single dose


Oral clearance of lorazepam reduced by 20


150 mg twice daily

Cmax and AUC of free valproic acid at steady-state was decreased by 10-12

Lithium Up to 2400 mgday given in twice daily doses


No effect on steady-state pharmacokinetics of lithium

Antipyrine 1 g single dose


No effect on clearance of antipyrine or urinary recovery of its metabolites

13 NONCLINICAL TOXICOLOGY

131 Carcinogenesis Mutagenesis Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in C57BL mice and Wistar rats Quetiapine was administered in the diet to mice at doses of 20 75 250 and 750 mgkg and to rats by gavage at doses of 25 75 and 250 mgkg for two years These doses are equivalent to 01 05 15 and 45 times the MRHD of 800 mgday based on mgm2 body surface area (mice) or 03 1 and 3 times the MRHD based on mgm2 body surface area (rats) There were statistically significant increases in thyroid gland follicular adenomas in male mice at doses 15 and 45 times the MRHD based on mgm2 body surface area and in male rats at a dose of 3 times the MRHD on mgm2 body surface area Mammary gland adenocarcinomas were statistically significantly increased in female rats at all doses tested (03 1 and 3 times the MRHD based on mgm2 body surface area)

Thyroid follicular cell adenomas may have resulted from chronic stimulation of the thyroid gland by thyroid stimulating hormone (TSH) resulting from enhanced metabolism and clearance of thyroxine by rodent liver Changes in TSH thyroxine and thyroxine clearance consistent with this mechanism were observed in subchronic toxicity studies in rat and mouse and in a 1-year toxicity study in rat however the results of these studies were not definitive The relevance of the increases in thyroid follicular cell adenomas to human risk through whatever mechanism is unknown

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents Serum measurements in a 1-year toxicity study showed that quetiapine increased median serum prolactin levels a maximum of 32- and 13-fold in male and female rats respectively Increases in mammary neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and are considered to be prolactin-mediated The relevance of this increased incidence of prolactin-mediated mammary gland tumors in rats to human risk is unknown [see Warnings and Precautions (515)]

Mutagenesis Quetiapine was not mutagenic or clastogenic in standard genotoxicity tests The mutagenic potential of quetiapine was tested in the in vitro Ames bacterial gene mutation assay and in the in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells The clastogenic potential of quetiapine was tested in the in vitro chromosomal aberration assay in cultured human lymphocytes and in the in vivo bone marrow micronucleus assay in rats up to 500 mgkg which is 6 times the maximum recommended human dose based on mgm2 body surface area

Impairment of Fertility Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mgkg or approximately 1 and 3 times the MRHD of 800 mgday based on mgm2 body surface area Drug-related effects included increases in interval to mate and in the number of matings required for successful impregnation These effects continued to be observed at 3 times the MRHD even after a two-week period without treatment The no-effect dose for impaired mating and fertility in male rats was 25 mgkg or 03 times the MRHD dose based on mgm2 body surface area Quetiapine adversely affected mating and fertility in female Sprague-Dawley rats at an oral dose approximately 1 times the MRHD of 800 mgday based on mgm2 body surface area Drug-related effects included decreases in matings and in matings resulting in pregnancy and an increase in the interval to mate An increase in irregular estrus cycles was observed at doses of 10 and 50 mgkg or approximately 01 and 1 times the MRHD of 800 mgday based on mgm2 body surface area The no-effect dose in female rats was 1 mgkg or 001 times the MRHD of 800 mgday based on mgm2 body surface area

132 Animal Toxicology andor Pharmacology Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2-year carcinogenicity study Doses were 10 25 50 75 150 and 250 mgkg in rat studies which are approximately 01 03 06 1 2 and 3-times the MRHD of 800 mgday based on mgm2 body surface area respectively Doses in the mouse carcinogenicity study were 20 75 250 and 750 mgkg which are approximately

01 05 15 and 45 times the MRHD of 800 mgday based on mgm2 body surface area Pigment deposition was shown to be irreversible in rats The identity of the pigment could not be determined but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells The functional effects and the relevance of this finding to human risk are unknown

In dogs receiving quetiapine for 6 or 12 months but not for 1-month focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mgkg or 4 times the MRHD of 800 mgday based on mgm2 body surface area This finding may be due to inhibition of cholesterol biosynthesis by quetiapine Quetiapine caused a dose-related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies however there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs The appearance of delta-8shycholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species There also was a 25 reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs Drug-related cataracts have not been seen in any other species however in a 1-year study in monkeys a striated appearance of the anterior lens surface was detected in 27 females at a dose of 225 mgkg or 55 times the MRHD of 800 mgday based on mgm2 body surface area

14 CLINICAL STUDIES

141 Schizophrenia Short-term Trials-Adults The efficacy of SEROQUEL in the treatment of schizophrenia was established in 3 short-term (6-week) controlled trials of inpatients with schizophrenia who met DSM III-R criteria for schizophrenia Although a single fixed dose haloperidol arm was included as a comparative treatment in one of the three trials this single haloperidol dose group was inadequate to provide a reliable and valid comparison of SEROQUEL and haloperidol

Several instruments were used for assessing psychiatric signs and symptoms in these studies among them the Brief Psychiatric Rating Scale (BPRS) a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia The BPRS psychosis cluster (conceptual disorganization hallucinatory behavior suspiciousness and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients A second traditional assessment the Clinical Global Impression (CGI) reflects the impression of a skilled observer fully familiar with the manifestations of schizophrenia about the overall clinical state of the patient

The results of the trials follow

1 In a 6-week placebo-controlled trial (n=361) (study 1) involving 5 fixed doses of SEROQUEL (75 mgday 150 mgday 300 mgday 600 mgday and 750 mgday given in divided doses three times per day) the 4 highest doses of SEROQUEL were generally superior to placebo on the BPRS total score the BPRS psychosis cluster and the CGI severity score with the maximal effect seen at 300 mgday and the effects of doses of 150 mgday to 750 mgday were generally indistinguishable

2 In a 6-week placebo-controlled trial (n=286) (study 2) involving titration of SEROQUEL in high (up to 750 mgday given in divided doses three times per day) and low (up to 250 mgday given in divided doses three times per day) doses only the high dose SEROQUEL group (mean dose 500 mgday) was superior to placebo on the BPRS total score the BPRS psychosis cluster and the CGI severity score

3 In a 6-week dose and dose regimen comparison trial (n=618) (study 3) involving two fixed doses of SEROQUEL (450 mgday given in divided doses both twice daily and three times daily and 50 mgday given in divided doses twice daily) only the 450 mgday (225 mg given twice daily) dose group was superior to the 50 mgday (25 mg given twice daily) SEROQUEL dose group on the BPRS total score the BPRS psychosis cluster and the CGI severity score

The primary efficacy results of these three studies in the treatment of schizophrenia in adults is presented in Table 19

Examination of population subsets (race gender and age) did not reveal any differential responsiveness on the basis of race or gender with an apparently greater effect in patients under the age of 40 years compared to those older than 40 The clinical significance of this finding is unknown

Adolescents (ages 13-17) The efficacy of SEROQUEL in the treatment of schizophrenia in adolescents (13-17 years of age) was demonstrated in a 6-week double-blind placebo-controlled trial (study 4) Patients who met DSM-IV diagnostic criteria for schizophrenia were randomized into one of three treatment groups SEROQUEL 400 mgday (n=73) SEROQUEL 800 mgday (n=74) or placebo (n=75) Study medication was initiated at 50 mgday and on day 2 increased to 100 mgper day (divided and given two or three times per day) Subsequently the dose was titrated to the target dose of 400 mgday or 800 mgday using increments of 100 mgday divided and given two or three times daily The primary efficacy variable was the mean change from baseline in total Positive and Negative Syndrome Scale (PANSS)

SEROQUEL at 400 mgday and 800 mgday was superior to placebo in the reduction of PANSS total score The primary efficacy results of this study in the treatment of schizophrenia in adolescents is presented in Table 19

Table 19 Schizophrenia Short-Term Trials

Study Number

Treatment Group Primary Efficacy Endpoint BPRS Total Mean Baseline

Score (SD) LS Mean Change

from Baseline (SE) Placebo-subtracted

Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3

SEROQUEL (450 mgday BID) 421 (107) -100 (13) -46 (-78 -14)

SEROQUEL (450 mgday TID)3 427 (104) -86 (13) -32 (-64 00)

SEROQUEL (50 mg BID) 417 (100) -54 (13) -shyPrimary Efficacy Endpoint PANSS Total

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Difference1 (95 CI)

Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

Placebo 962 (177) -192 (30) -shySD standard deviation SE standard error LS Mean least-squares mean CI unadjusted confidence interval 1 Difference (drug minus placebo) in least-squares mean change from baseline 2 Doses that are statistically significant superior to placebo 3 Doses that are statistically significant superior to SEROQUEL 50 mg BID

142 Bipolar Disorder Bipolar I disorder manic or mixed episodes

Adults The efficacy of SEROQUEL in the acute treatment of manic episodes was established in 3 placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder with manic episodes These trials included patients with or without psychotic features and excluded patients with rapid cycling and mixed episodes Of these trials 2 were monotherapy (12 weeks) and 1 was adjunct therapy (3 weeks) to either lithium or divalproex Key outcomes in these trials were change from baseline in the Young Mania Rating Scale (YMRS) score at 3 and 12 weeks for monotherapy and at 3 weeks for adjunct therapy Adjunct therapy is defined as the simultaneous initiation or subsequent administration of SEROQUEL with lithium or divalproex

The primary rating instrument used for assessing manic symptoms in these trials was YMRS an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability disruptiveaggressive behavior sleep elevated mood speech increased activity sexual interest languagethought disorder thought content appearance and insight) in a range from 0 (no manic features) to 60 (maximum score)


Monotherapy The efficacy of SEROQUEL in the acute treatment of bipolar mania was established in 2 placebo-controlled trials In two 12-week trials (n=300 n=299) comparing SEROQUEL to placebo SEROQUEL was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12 The majority of patients in these trials taking SEROQUEL were dosed in a range between 400 mgday and 800 mg per day (studies 1 and 2 in Table 20)

Adjunct Therapy In this 3-week placebo-controlled trial 170 patients with bipolar mania (YMRS ge20) were randomized to receive SEROQUEL or placebo as adjunct treatment to lithium or divalproex Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization SEROQUEL was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score (study 3 in Table 20)

The majority of patients in this trial taking SEROQUEL were dosed in a range between 400 mgday and 800 mg per day In a similarly designed trial (n=200) SEROQUEL was associated with an improvement in YMRS scores but did not demonstrate superiority to placebo possibly due to a higher placebo effect

The primary efficacy results of these studies in the treatment of mania in adults is presented in Table 20

Children and Adolescents (ages 10-17)

The efficacy of SEROQUEL in the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10-17 years of age) was demonstrated in a 3-week double-blind placebo-controlled multicenter trial (study 4 in Table 20) Patients who met DSM-IV diagnostic criteria for a manic episode were randomized into one of three treatment groups SEROQUEL 400 mgday (n=95) SEROQUEL 600 mgday (n=98) or placebo (n=91) Study medication was initiated at 50 mgday and on day 2 increased to 100 mgday (divided doses given two or three times daily) Subsequently the dose was titrated to a target dose of 400 mgday or 600 mgday using increments of 100 mgday given in divided doses two or three times daily The primary efficacy variable was the mean change from baseline in total YMRS score

SEROQUEL 400 mgday and 600 mgday were superior to placebo in the reduction of YMRS total score (Table 20)

Table 20 Mania Trials

Study Treatment Group Primary Efficacy Measure YMRS Total Number Mean Baseline

Score (SD)4 LS Mean Change


Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy

Study 3 SEROQUEL (200-800 mgday)1 + mood stabilizer 315 (58) -138 (16) -38 (-71 -06)

Placebo + mood stabilizer 311 (55) -10 (15) -shy

SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)

Study 4 SEROQUEL (600 mgday)1 296 (64) -156 (097) -66 (-95 -37)

Placebo 307 (59) -90 (11) -shyMood stabilizer lithium or divalproex SD standard deviation SE standard error LS Mean least-squares mean CI unadjusted confidence interval 1 Doses that are statistically significantly superior to placebo 2 Difference (drug minus placebo) in least-squares mean change from baseline 3 Included in the trial as an active comparator 4 Adult data mean baseline score is based on patients included in the primary analysis pediatric mean baseline score is based on all patients in the

ITT population

Bipolar Disorder Depressive Episodes Adults The efficacy of SEROQUEL for the acute treatment of depressive episodes associated with bipolar disorder was established in 2 identically designed 8-week randomized double-blind placebo-controlled studies (N=1045) (studies 5 and 6 in Table 21) These studies included patients with either bipolar I or II disorder and those with or without a rapid cycling course Patients randomized to SEROQUEL were administered fixed doses of either 300 mg or 600 mg once daily

The primary rating instrument used to assess depressive symptoms in these studies was the Montgomery-Asberg Depression Rating Scale (MADRS) a 10-item clinician-rated scale with scores ranging from 0 to 60 The primary endpoint in both studies was the change from baseline in MADRS score at week 8 In both studies SEROQUEL was superior to placebo in reduction of MADRS score Improvement in symptoms as measured by change in MADRS score relative to placebo was seen in both studies at Day 8 (week 1) and onwards In these studies no additional benefit was seen with the 600 mg dose For the 300 mg dose group statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning as measured using the Q-LES-Q(SF)

The primary efficacy results of these studies in the acute treatment of depressive episodes associated with bipolar disorder in adults is presented in Table 21

Table 21 Depressive Episodes Associated with Bipolar Disorder

Study Treatment Group Primary Efficacy Measure MADRS Total Number Mean Baseline



Difference2 (95 CI) SEROQUEL (300 mgday)1 303 (50) -164 (09) -61 (-83 -39)

Study 5 SEROQUEL (600 mgday)1 303 (53) -167 (09) -65 (-87 -43) Placebo 306 (53) -103 (09) -shy

Study 6 SEROQUEL (300 mgday)1 311 (57) -169 (10) -50 (-73 -27) SEROQUEL (600 mgday)1 299 (56) -160 (10) -41 (-64 -18)

Placebo 296 (54) -119 (10) -shySD standard deviation SE standard error LS Mean least-squares mean CI unadjusted confidence interval 1 Doses that are statistically significantly superior to placebo 2 Difference (drug minus placebo) in least-squares mean change from baseline

Maintenance Treatment as an Adjunct to Lithium or Divalproex

The efficacy of SEROQUEL in the maintenance treatment of bipolar I disorder was established in 2 placebo-controlled trials in patients (n=1326) who met DSM-IV criteria for bipolar I disorder (studies 7 and 8 in Figures 1 and 2) The trials included patients whose most recent episode was manic depressed or mixed with or without psychotic features In the open-label phase patients were required to be stable on SEROQUEL plus lithium or divalproex for at least 12 weeks in order to be randomized On average patients were stabilized for 15 weeks In the randomization phase patients continued treatment with lithium or divalproex and were randomized to receive either SEROQUEL (administered twice daily totaling 400 mgday to 800 mgday) or placebo Approximately 50 of the patients had discontinued from the SEROQUEL group by day 280 and 50 of the placebo group had discontinued by day 117 of double-blind treatment The primary endpoint in these studies was time to recurrence of a mood event (manic mixed or depressed episode) A mood event was defined as medication initiation or hospitalization for a mood episode YMRS scorege20 or MADRS scorege20 at 2 consecutive assessments or study discontinuation due to a mood event (Figure 1 and Figure 2)

In both studies SEROQUEL was superior to placebo in increasing the time to recurrence of any mood event The treatment effect was present for increasing time to recurrence of both manic and depressed episodes The effect of SEROQUEL was independent of any specific subgroup (assigned mood stabilizer sex age race most recent bipolar episode or rapid cycling course)

Figure 1 Kaplan-Meier Curves of Time to Recurrence of a Mood Event (Study 7)


16 HOW SUPPLIEDSTORAGE AND HANDLING

25 mg Tablets (NDC 0310-0275-10) peach round biconvex film coated tablets identified with lsquoSEROQUELrsquo and lsquo25rsquo on one side and plain on the other side are supplied in bottles of 100 tablets

50 mg Tablets (NDC 0310-0278-10) white round biconvex film coated tablets identified with lsquoSEROQUELrsquo and lsquo50rsquo on one side and plain on the other side are supplied in bottles of 100 tablets

100 mg Tablets (NDC 0310-0271-10) yellow round biconvex film coated tablets identified with lsquoSEROQUELrsquo and lsquo100rsquo on one side and plain on the other side are supplied in bottles of 100 tablets


300 mg Tablets (NDC 0310-0274-60) white capsule-shaped biconvex film coated tablets intagliated with lsquoSEROQUELrsquo on one side and lsquo300rsquo on the other side are supplied in bottles of 60 tablets

400 mg Tablets (NDC 0310-0279-10) yellow capsule-shaped biconvex film coated tablets intagliated with lsquoSEROQUELrsquo on one side and lsquo400rsquo on the other side are supplied in bottles of 100 tablets

Store at 25ordmC (77ordmF) excursions permitted to 15-30ordmC (59-86ordmF) [See USP]

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking SEROQUEL

Increased Mortality in Elderly Patients with Dementia-Related Psychosis Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at increased risk of death compared with placebo Quetiapine is not approved for elderly patients with dementia-related psychosis [see Warnings and Precautions (51)]

Suicidal Thoughts and Behaviors Patients their families and their caregivers should be encouraged to be alert to the emergence of anxiety agitation panic attacks insomnia irritability hostility aggressiveness impulsivity akathisia (psychomotor restlessness) hypomania mania other unusual changes in behavior worsening of depression and suicidal ideation especially early during antidepressant treatment and when the dose is adjusted up or down Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis since changes may be abrupt Such symptoms should be reported to the patients prescriber or health professional especially if they are severe abrupt in onset or were not part of the patients presenting symptoms Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Warnings and Precautions (52)]

Neuroleptic Malignant Syndrome (NMS) Patients should be advised to report to their physician any signs or symptoms that may be related to NMS These may include muscle stiffness and high fever [see Warnings and Precautions (54)]

Hyperglycemia and Diabetes Mellitus Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus Patients who are diagnosed with diabetes those with risk factors for diabetes or those that develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment [see Warnings and Precautions (55)]

Hyperlipidemia Patients should be advised that elevations in total cholesterol LDL-cholesterol and triglycerides and decreases in HDL-cholesterol may occur Patients should have their lipid profile monitored at the beginning of and periodically during treatment [see Warnings and Precautions (55)]

Weight Gain Patients should be advised that they may experience weight gain Patients should have their weight monitored regularly [see Warnings and Precautions (55)]

Orthostatic Hypotension Patients should be advised of the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing which may lead to falls) especially during the period of initial dose titration and also at times of re-initiating treatment or increases in dose [see Warnings and Precautions (57)]

Increased Blood Pressure in Children and Adolescents Children and adolescent patients should have their blood pressure measured at the beginning of and periodically during treatment [see Warnings and Precautions (59)]

LeukopeniaNeutropenia Patients with a pre-existing low WBC or a history of drug induced leukopenianeutropenia should be advised that they should have their CBC monitored while taking SEROQUEL Patients should be advised to talk to their doctor as soon as possible if they have a fever flu-like symptoms sore throat or any other infection as this could be a result of a very low

WBC which may require SEROQUEL to be stopped andor treatment to be given [see Warnings and Precautions (510)]

Interference with Cognitive and Motor Performance Patients should be advised of the risk of somnolence or sedation (which may lead to falls) especially during the period of initial dose titration Patients should be cautioned about performing any activity requiring mental alertness such as operating a motor vehicle (including automobiles) or operating machinery until they are reasonably certain quetiapine therapy does not affect them adversely [see Warnings and Precautions (516)]

Heat Exposure and Dehydration Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (517)]

Concomitant Medication As with other medications patients should be advised to notify their physicians if they are taking or plan to take any prescription or over-the-counter drugs [see Drug Interactions (71)]

Pregnancy Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with SEROQUEL Advise patients that SEROQUEL may cause extrapyramidal andor withdrawal symptoms (agitation hypertonia hypotonia tremor somnolence respiratory distress and feeding disorder) in a neonate Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to SEROQUEL during pregnancy [see Use in Specific Populations (81)]

Infertility Advise females of reproductive potential that SEROQUEL may impair fertility due to an increase in serum prolactin levels The effects on fertility are reversible [see Use in Specific Populations (83)]

Need for Comprehensive Treatment Program SEROQUEL is indicated as an integral part of a total treatment program for adolescents with schizophrenia and pediatric bipolar disorder that may include other measures (psychological educational and social) Effectiveness and safety of SEROQUEL have not been established in pediatric patients less than 13 years of age for schizophrenia or less than 10 years of age for bipolar mania Appropriate educational placement is essential and psychosocial intervention is often helpful The decision to prescribe atypical antipsychotic medication will depend upon the physicianrsquos assessment of the chronicity and severity of the patientrsquos symptoms [see Indications and Usage (13)]

Medication Guide SEROQUEL (SER-oh-kwell)

(quetiapine) Tablets

Read this Medication Guide before you start taking SEROQUEL and each time you get a refill There may be new information This information does not take the place of talking to your healthcare provider about your medical condition or your treatment What is the most important information I should know about SEROQUEL

SEROQUEL may cause serious side effects including

1 risk of death in the elderly with dementia Medicines like SEROQUEL can increase the risk of death in elderly people who have memory loss (dementia) SEROQUEL is not for treating psychosis in the elderly with dementia

2 risk of suicidal thoughts or actions (antidepressant medicines depression and other serious mental illnesses and suicidal thoughts or actions)

bull Talk to your or your family memberrsquos healthcare provider about ∘ all risks and benefits of treatment with antidepressant medicines ∘ all treatment choices for depression or other serious mental illness

bull Antidepressant medications may increase suicidal thoughts or actions in some children teenagers and young adults within the first few months of treatment

bull Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions Some people may have a particularly high risk of having suicidal thoughts or actions These include people who have (or have a family history of) depression bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions

bull How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member

∘ Pay close attention to any changes especially sudden changes in mood behaviors thoughts or feelings This is very important when an antidepressant medicine is started or when the dose is changed

∘ Call the healthcare provider right away to report new or sudden changes in mood behavior thoughts or feelings ∘ Keep all follow-up visits with the healthcare provider as scheduled Call the healthcare provider between visits as

needed especially if you have concerns about symptoms

Call a healthcare provider right away if you or your family member has any of the following symptoms especially if they are new worse or worry you

bull thoughts about suicide or dying bull attempts to commit suicide bull new or worse depression bull new or worse anxiety bull feeling very agitated or restless bull panic attacks bull trouble sleeping (insomnia) bull new or worse irritability bull acting aggressive being angry or violent bull acting on dangerous impulses bull an extreme increase in activity and talking (mania)

bull other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines

bull Never stop an antidepressant medicine without first talking to your healthcare provider Stopping an antidepressant medicine suddenly can cause other symptoms

bull Antidepressants are medicines used to treat depression and other illnesses It is important to discuss all the risks of treating depression and also the risks of not treating it Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider not just the use of antidepressants

bull Antidepressant medicines have other side effects Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member

bull Antidepressant medicines can interact with other medicines Know all of the medicines that you or your family member take Keep a list of all medicines to show the healthcare provider Do not start new medicines without first checking with your healthcare provider

bull Not all antidepressant medicines prescribed for children are FDA approved for use in children Talk to your childrsquos healthcare provider for more information

What is SEROQUEL SEROQUEL is a prescription medicine used to treat

bull schizophrenia in people 13 years of age or older bull bipolar disorder in adults including ∘ depressive episodes associated with bipolar disorder ∘ manic episodes associated with bipolar I disorder alone or with lithium or divalproex ∘ long-term treatment of bipolar I disorder with lithium or divalproex

bull manic episodes associated with bipolar I disorder in children ages 10-17 years old

It is not known if SEROQUEL is safe and effective in children under 10 years of age

What should I tell my healthcare provider before taking SEROQUEL

Before you take SEROQUEL tell your healthcare provider if you have or have had

bull diabetes or high blood sugar in you or your family Your healthcare provider should check your blood sugar before you start SEROQUEL and also during therapy

bull high levels of total cholesterol triglycerides or LDL-cholesterol or low levels of HDL-cholesterol bull low or high blood pressure bull low white blood cell count bull cataracts bull seizures bull abnormal thyroid tests bull high prolactin levels bull heart problems bull liver problems bull any other medical condition bull pregnancy or plans to become pregnant It is not known if SEROQUEL will harm your unborn baby bull If you become pregnant while receiving SEROQUEL talk to your healthcare provider about registering with the

National Pregnancy Registry for Atypical Antipsychotics You can register by calling 1-866-961-2388 or go to httpwomensmentalhealthorgclinical-and-research-programspregnancyregistry

bull breast-feeding or plans to breast-feed SEROQUEL can pass into your breast milk Talk to your healthcare provider about the best way to feed your baby if you receive SEROQUEL

bull if you have or have had a condition where you cannot completely empty your bladder (urinary retention) have an enlarged prostate or constipation or increased pressure inside your eyes

Tell the healthcare provider about all the medicines that you take or recently have taken including prescription medicines over-the-counter medicines herbal supplements and vitamins

SEROQUEL and other medicines may affect each other causing serious side effects SEROQUEL may affect the way other medicines work and other medicines may affect how SEROQUEL works

Tell your healthcare provider if you are having a urine drug screen because SEROQUEL may affect your test results Tell those giving the test that you are taking SEROQUEL

How should I take SEROQUEL

bull Take SEROQUEL exactly as your healthcare provider tells you to take it Do not change the dose yourself bull Take SEROQUEL by mouth with or without food bull If you feel you need to stop SEROQUEL talk with your healthcare provider first If you suddenly stop taking

SEROQUEL you may have side effects such as trouble sleeping or trouble staying asleep (insomnia) nausea and vomiting

bull If you miss a dose of SEROQUEL take it as soon as you remember If you are close to your next dose skip the missed dose Just take the next dose at your regular time Do not take 2 doses at the same time unless your healthcare provider tells you to If you are not sure about your dosing call your healthcare provider

What should I avoid while taking SEROQUEL

bull Do not drive operate machinery or do other dangerous activities until you know how SEROQUEL affects you SEROQUEL may make you drowsy

bull Avoid getting overheated or dehydrated ∘ Do not over-exercise ∘ In hot weather stay inside in a cool place if possible ∘ Stay out of the sun Do not wear too much or heavy clothing ∘ Drink plenty of water

bull Do not drink alcohol while taking SEROQUEL It may make some side effects of SEROQUEL worse

What are possible side effects of SEROQUEL

SEROQUEL can cause serious side effects including

bull See ldquoWhat is the most important information I should know about SEROQUELrdquo bull stroke that can lead to death can happen in elderly people with dementia who take medicines like SEROQUEL bull neuroleptic malignant syndrome (NMS) NMS is a rare but very serious condition that can happen in people who

take antipsychotic medicines including SEROQUEL NMS can cause death and must be treated in a hospital Call your healthcare provider right away if you become severely ill and have some or all of these symptoms ∘ high fever ∘ excessive sweating ∘ rigid muscles ∘ confusion ∘ changes in your breathing heartbeat and blood pressure

bull falls can happen in some people who take SEROQUEL These falls may cause serious injuries bull high blood sugar (hyperglycemia) High blood sugar can happen if you have diabetes already or if you have never

had diabetes High blood sugar could lead to ∘ build-up of acid in your blood due to ketones (ketoacidosis) ∘ coma ∘ death Increases in blood sugar can happen in some people who take SEROQUEL Extremely high blood sugar can lead to coma or death If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes) your healthcare provider should check your blood sugar before you start SEROQUEL and during therapy Call your healthcare provider if you have any of these symptoms of high blood sugar (hyperglycemia) while taking SEROQUEL ∘ feel very thirsty ∘ need to urinate more than usual ∘ feel very hungry ∘ feel weak or tired ∘ feel sick to your stomach ∘ feel confused or your breath smells fruity

bull high fat levels in your blood (increased cholesterol and triglycerides) High fat levels may happen in people treated with SEROQUEL You may not have any symptoms so your healthcare provider may decide to check your cholesterol and triglycerides during your treatment with SEROQUEL

bull increase in weight (weight gain) Weight gain is common in people who take SEROQUEL so you and your healthcare provider should check your weight regularly Talk to your healthcare provider about ways to control weight gain such as eating a healthy balanced diet and exercising

bull movements you cannot control in your face tongue or other body parts (tardive dyskinesia) These may be signs of a serious condition Tardive dyskinesia may not go away even if you stop taking SEROQUEL Tardive dyskinesia may also start after you stop taking SEROQUEL

bull decreased blood pressure (orthostatic hypotension) including lightheadedness or fainting caused by a sudden change in heart rate and blood pressure when rising too quickly from a sitting or lying position

bull increases in blood pressure in children and teenagers Your healthcare provider should check blood pressure in children and adolescents before starting SEROQUEL and during therapy

bull low white blood cell count Tell your healthcare provider as soon as possible if you have a fever flu-like symptoms or any other infection as this could be a result of a very low white blood cell count Your healthcare provider may check your white blood cell level to determine if further treatment or other action is needed

bull cataracts bull seizures bull abnormal thyroid tests Your healthcare provider may do blood tests to check your thyroid hormone level bull increases in prolactin levels bull sleepiness drowsiness feeling tired difficulty thinking and doing normal activities bull increased body temperature bull difficulty swallowing bull trouble sleeping or trouble staying asleep (insomnia) nausea or vomiting if you suddenly stop taking

SEROQUEL These symptoms usually get better 1 week after you start having them The most common side effects of SEROQUEL include In Adults bull drowsiness bull sudden drop in blood pressure upon standing

bull weight gain bull sluggishness bull abnormal liver tests bull upset stomach bull dry mouth bull dizziness bull weakness bull abdominal pain bull constipation bull sore throat In Children and Adolescents bull drowsiness bull dizziness bull fatigue bull nausea bull dry mouth bull weight gain bull increased appetite bull vomiting bull rapid heart beat

These are not all the possible side effects of SEROQUEL For more information ask your healthcare provider or pharmacist Call your doctor for medical advice about side effects You may report side effects to FDA at 1-800-FDA-1088

How should I store SEROQUEL

bull Store SEROQUEL at room temperature between 68degF to 77degF (20degC to 25degC) bull Keep SEROQUEL and all medicines out of the reach of children

General information about the safe and effective use of SEROQUEL

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide Do not use SEROQUEL for a condition for which it was not prescribed Do not give SEROQUEL to other people even if they have the same symptoms you have It may harm them

This Medication Guide summarizes the most important information about SEROQUEL If you would like more information talk with your healthcare provider You can ask your pharmacist or healthcare provider for information about SEROQUEL that is written for health professionals

For more information go to wwwSEROQUELcom or call 1-800-236-9933

What are the ingredients in SEROQUEL

Active ingredient quetiapine Inactive ingredients povidone dibasic dicalcium phosphate dihydrate microcrystalline cellulose sodium starch glycolate lactose monohydrate magnesium stearate hypromellose polyethylene glycol and titanium dioxide The 25 mg tablets contain red and yellow ferric oxide The 100 mg and 400 mg tablets contain only yellow ferric oxide

This Medication Guide has been approved by the US Food and Drug Administration

SEROQUEL is a registered trademark of the AstraZeneca group of companies copyAstraZeneca 2019 Distributed by AstraZeneca Pharmaceuticals LP Wilmington DE 19850 Revised 032020

David Digitally signed by David Lewis Date 3272020 014647PMLewis GUID 508da72000029f287fa31e664741b577

WARNING INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS AND SUICIDAL THOUGHTS AND BEHAVIORS 1 INDICATIONS AND USAGE

11 Schizophrenia 12 Bipolar Disorder 13 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder

2 DOSAGE AND ADMINISTRATION 21 Important Administration Instructions 22 Recommended Dosing 23 Dose Modifications in Elderly Patients 24 Dose Modifications in Hepatically Impaired Patients 25 Dose Modifications when used with CYP3A4 Inhibitors 26 Dose Modifications when used with CYP3A4 Inducers 27 Re-initiation of Treatment in Patients Previously Discontinued 28 Switching from Antipsychotics

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

51 Increased Mortality in Elderly Patients with Dementia-Related Psychosis 52 Suicidal Thoughts and Behaviors in Adolescents and Young Adults 53 Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis 54 Neuroleptic Malignant Syndrome (NMS) 55 Metabolic Changes 56 Tardive Dyskinesia 57 Hypotension 58 Falls 59 Increases in Blood Pressure (Children and Adolescents) 510 Leukopenia Neutropenia and Agranulocytosis 511 Cataracts 512 QT Prolongation 513 Seizures 514 Hypothyroidism 515 Hyperprolactinemia 516 Potential for Cognitive and Motor Impairment

517 Body Temperature Regulation 518 Dysphagia 519 Discontinuation Syndrome 520 Anticholinergic (antimuscarinic) Effects

6 ADVERSE REACTIONS 61 Clinical Study Experience 62 Postmarketing Experience

7 DRUG INTERACTIONS 71 Effect of Other Drugs on Quetiapine 72 Effect of Quetiapine on Other Drugs

8 USE IN SPECIFIC POPULATIONS 81 Pregnancy 82 Lactation 83 Females and Males of Reproductive Potential 84 Pediatric Use 85 Geriatric Use 86 Renal Impairment 87 Hepatic Impairment

9 DRUG ABUSE AND DEPENDENCE 91 Controlled Substance 92 Abuse

10 OVERDOSAGE 101 Human Experience 102 Management of Overdosage

11 DESCRIPTION 12 CLINICAL PHARMACOLOGY

121 Mechanism of Action 122 Pharmacodynamics 123 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY 131 Carcinogenesis Mutagenesis Impairment of Fertility 132 Animal Toxicology andor Pharmacology

14 CLINICAL STUDIES 141 Schizophrenia 142 Bipolar Disorder

16 HOW SUPPLIEDSTORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed































300 mgday 300 mgday



















4 CONTRAINDICATIONS











25-64 1 fewer case

ge65 6 fewer cases


















Adults


Laboratory Analyte





Fasting Glucose




Placebo 279 33 (118)







Dyslipidemia



Laboratory Analyte




Placebo 92 6 (7)

Bipolar Depression2

SEROQUEL 463 41 (9)

Placebo 250 15 (6)



Placebo 70 11 (16)

Bipolar Depression2


Placebo 232 20 (9)



Placebo na3 na3

Bipolar Depression2

SEROQUEL 465 29 (6)

Placebo 256 12 (5)



Placebo na3 na3

Bipolar Depression2





Laboratory Analyte





Placebo 66 2 (3)
















n () SEROQUEL 391 89 (23)

Schizophrenia1

Placebo 206 11 (6)


Weight



Placebo 198 13 (7)



Placebo 203 8 (4)


Placebo 295 7 (2)





n ()



Placebo 44 3 (7)



































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population

















































































































































300 mgday 300 mgday



















4 CONTRAINDICATIONS











25-64 1 fewer case

ge65 6 fewer cases


















Adults


Laboratory Analyte





Fasting Glucose




Placebo 279 33 (118)







Dyslipidemia



Laboratory Analyte




Placebo 92 6 (7)

Bipolar Depression2

SEROQUEL 463 41 (9)

Placebo 250 15 (6)



Placebo 70 11 (16)

Bipolar Depression2


Placebo 232 20 (9)



Placebo na3 na3

Bipolar Depression2

SEROQUEL 465 29 (6)

Placebo 256 12 (5)



Placebo na3 na3

Bipolar Depression2





Laboratory Analyte





Placebo 66 2 (3)
















n () SEROQUEL 391 89 (23)

Schizophrenia1

Placebo 206 11 (6)


Weight



Placebo 198 13 (7)



Placebo 203 8 (4)


Placebo 295 7 (2)





n ()



Placebo 44 3 (7)



































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population






































































































































300 mgday 300 mgday



















4 CONTRAINDICATIONS











25-64 1 fewer case

ge65 6 fewer cases


















Adults


Laboratory Analyte





Fasting Glucose




Placebo 279 33 (118)







Dyslipidemia



Laboratory Analyte




Placebo 92 6 (7)

Bipolar Depression2

SEROQUEL 463 41 (9)

Placebo 250 15 (6)



Placebo 70 11 (16)

Bipolar Depression2


Placebo 232 20 (9)



Placebo na3 na3

Bipolar Depression2

SEROQUEL 465 29 (6)

Placebo 256 12 (5)



Placebo na3 na3

Bipolar Depression2





Laboratory Analyte





Placebo 66 2 (3)
















n () SEROQUEL 391 89 (23)

Schizophrenia1

Placebo 206 11 (6)


Weight



Placebo 198 13 (7)



Placebo 203 8 (4)


Placebo 295 7 (2)





n ()



Placebo 44 3 (7)



































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population
























































































































300 mgday 300 mgday



















4 CONTRAINDICATIONS











25-64 1 fewer case

ge65 6 fewer cases


















Adults


Laboratory Analyte





Fasting Glucose




Placebo 279 33 (118)







Dyslipidemia



Laboratory Analyte




Placebo 92 6 (7)

Bipolar Depression2

SEROQUEL 463 41 (9)

Placebo 250 15 (6)



Placebo 70 11 (16)

Bipolar Depression2


Placebo 232 20 (9)



Placebo na3 na3

Bipolar Depression2

SEROQUEL 465 29 (6)

Placebo 256 12 (5)



Placebo na3 na3

Bipolar Depression2





Laboratory Analyte





Placebo 66 2 (3)
















n () SEROQUEL 391 89 (23)

Schizophrenia1

Placebo 206 11 (6)


Weight



Placebo 198 13 (7)



Placebo 203 8 (4)


Placebo 295 7 (2)





n ()



Placebo 44 3 (7)



































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population

































































































































4 CONTRAINDICATIONS











25-64 1 fewer case

ge65 6 fewer cases


















Adults


Laboratory Analyte





Fasting Glucose




Placebo 279 33 (118)







Dyslipidemia



Laboratory Analyte




Placebo 92 6 (7)

Bipolar Depression2

SEROQUEL 463 41 (9)

Placebo 250 15 (6)



Placebo 70 11 (16)

Bipolar Depression2


Placebo 232 20 (9)



Placebo na3 na3

Bipolar Depression2

SEROQUEL 465 29 (6)

Placebo 256 12 (5)



Placebo na3 na3

Bipolar Depression2





Laboratory Analyte





Placebo 66 2 (3)
















n () SEROQUEL 391 89 (23)

Schizophrenia1

Placebo 206 11 (6)


Weight



Placebo 198 13 (7)



Placebo 203 8 (4)


Placebo 295 7 (2)





n ()



Placebo 44 3 (7)



































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population






















































































































4 CONTRAINDICATIONS











25-64 1 fewer case

ge65 6 fewer cases


















Adults


Laboratory Analyte





Fasting Glucose




Placebo 279 33 (118)







Dyslipidemia



Laboratory Analyte




Placebo 92 6 (7)

Bipolar Depression2

SEROQUEL 463 41 (9)

Placebo 250 15 (6)



Placebo 70 11 (16)

Bipolar Depression2


Placebo 232 20 (9)



Placebo na3 na3

Bipolar Depression2

SEROQUEL 465 29 (6)

Placebo 256 12 (5)



Placebo na3 na3

Bipolar Depression2





Laboratory Analyte





Placebo 66 2 (3)
















n () SEROQUEL 391 89 (23)

Schizophrenia1

Placebo 206 11 (6)


Weight



Placebo 198 13 (7)



Placebo 203 8 (4)


Placebo 295 7 (2)





n ()



Placebo 44 3 (7)



































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population
























































































































25-64 1 fewer case

ge65 6 fewer cases


















Adults


Laboratory Analyte





Fasting Glucose




Placebo 279 33 (118)







Dyslipidemia



Laboratory Analyte




Placebo 92 6 (7)

Bipolar Depression2

SEROQUEL 463 41 (9)

Placebo 250 15 (6)



Placebo 70 11 (16)

Bipolar Depression2


Placebo 232 20 (9)



Placebo na3 na3

Bipolar Depression2

SEROQUEL 465 29 (6)

Placebo 256 12 (5)



Placebo na3 na3

Bipolar Depression2





Laboratory Analyte





Placebo 66 2 (3)
















n () SEROQUEL 391 89 (23)

Schizophrenia1

Placebo 206 11 (6)


Weight



Placebo 198 13 (7)



Placebo 203 8 (4)


Placebo 295 7 (2)





n ()



Placebo 44 3 (7)



































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population





























































































































Adults


Laboratory Analyte





Fasting Glucose




Placebo 279 33 (118)







Dyslipidemia



Laboratory Analyte




Placebo 92 6 (7)

Bipolar Depression2

SEROQUEL 463 41 (9)

Placebo 250 15 (6)



Placebo 70 11 (16)

Bipolar Depression2


Placebo 232 20 (9)



Placebo na3 na3

Bipolar Depression2

SEROQUEL 465 29 (6)

Placebo 256 12 (5)



Placebo na3 na3

Bipolar Depression2





Laboratory Analyte





Placebo 66 2 (3)
















n () SEROQUEL 391 89 (23)

Schizophrenia1

Placebo 206 11 (6)


Weight



Placebo 198 13 (7)



Placebo 203 8 (4)


Placebo 295 7 (2)





n ()



Placebo 44 3 (7)



































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population




















































































































Adults


Laboratory Analyte





Fasting Glucose




Placebo 279 33 (118)







Dyslipidemia



Laboratory Analyte




Placebo 92 6 (7)

Bipolar Depression2

SEROQUEL 463 41 (9)

Placebo 250 15 (6)



Placebo 70 11 (16)

Bipolar Depression2


Placebo 232 20 (9)



Placebo na3 na3

Bipolar Depression2

SEROQUEL 465 29 (6)

Placebo 256 12 (5)



Placebo na3 na3

Bipolar Depression2





Laboratory Analyte





Placebo 66 2 (3)
















n () SEROQUEL 391 89 (23)

Schizophrenia1

Placebo 206 11 (6)


Weight



Placebo 198 13 (7)



Placebo 203 8 (4)


Placebo 295 7 (2)





n ()



Placebo 44 3 (7)



































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population




















































































































Dyslipidemia



Laboratory Analyte




Placebo 92 6 (7)

Bipolar Depression2

SEROQUEL 463 41 (9)

Placebo 250 15 (6)



Placebo 70 11 (16)

Bipolar Depression2


Placebo 232 20 (9)



Placebo na3 na3

Bipolar Depression2

SEROQUEL 465 29 (6)

Placebo 256 12 (5)



Placebo na3 na3

Bipolar Depression2





Laboratory Analyte





Placebo 66 2 (3)
















n () SEROQUEL 391 89 (23)

Schizophrenia1

Placebo 206 11 (6)


Weight



Placebo 198 13 (7)



Placebo 203 8 (4)


Placebo 295 7 (2)





n ()



Placebo 44 3 (7)



































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population



















































































































Placebo 66 2 (3)
















n () SEROQUEL 391 89 (23)

Schizophrenia1

Placebo 206 11 (6)


Weight



Placebo 198 13 (7)



Placebo 203 8 (4)


Placebo 295 7 (2)





n ()



Placebo 44 3 (7)



































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population























































































































n ()



Placebo 44 3 (7)



































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population












































































































































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population



































































































































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population


























































































































34 06 07 01 05 00 02 00 32 27 (371097) (4651) (527218) (43668) (2369) (0113) (115673) (12679) (2407587) (1053912)


















6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population






























































































































6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population























































































































6 ADVERSE REACTIONS










Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population

























































































































Bipolar Disorder










PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population























































































































PLACEBO (n=404)

Headache 21 14

Agitation 20 17

Somnolence 18 8

Dizziness 11 5

Dry Mouth 9 3

Constipation 8 3

Pain 7 5

Tachycardia 6 4

Vomiting 6 5

Asthenia 5 3

Dyspepsia 5 1

Weight Gain 5 1

ALT Increased 5 1

Anxiety 4 3

Pharyngitis 4 3

Rash 4 2

Abdominal Pain 4 1


Back Pain 3 1

AST Increased 3 1

Rhinitis 3 1

Fever 2 1

Gastroenteritis 2 0

Amblyopia 2 1





PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population






















































































































PLACEBO (n=203)

Somnolence 34 9

Dry Mouth 19 3

Headache 17 13

Asthenia 10 4

Constipation 10 5

Dizziness 9 6

Tremor 8 7

Abdominal Pain 7 3


Agitation 6 4

Weight Gain 6 3

Pharyngitis 6 3

Back Pain 5 3

Hypertonia 4 3

Rhinitis 4 2


Twitching 4 1

Dyspepsia 4 3

Depression 3 2

Amblyopia 3 2

Speech Disorder 3 1

Hypotension 3 1


3 0

Heaviness 2 1

Infection 2 1

Fever 2 1

Hypertension 2 1

Tachycardia 2 1


Hypothyroidism 2 1

Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population



















































































































Incoordination 2 1


Anxiety 2 0

Ataxia 2 0

Sinusitis 2 1

Sweating 2 1


2 1





PLACEBO (n=347)

Somnolence1 57 15

Dry Mouth 44 13

Dizziness 18 7

Constipation 10 4

Fatigue 10 8

Dyspepsia 7 4

Vomiting 5 4


Lethargy 5 2



Akathisia 4 1

Palpitations 4 1

Vision Blurred 4 2


Arthralgia 3 2

Paraesthesia 3 2

Cough 3 1


Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population



















































































































Irritability 3 1

Dysarthria 3 0

Hypersomnia 3 0


Abnormal Dreams 2 1

Tremor 2 1


2 1


Asthenia 2 1


Hypoesthesia 2 1

Dysphagia 2 0












Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population






















































































































Preferred Term

SEROQUEL 75 mgday

(N=53)

SEROQUEL 150 mgday

(N=48)

SEROQUEL 300 mgday

(N=52)

SEROQUEL 600 mgday

(N=51)

SEROQUEL 750 mgday



Parkinsonism 2 38 0 00 1 19 1 20 1 19 4 78

Akathisia 1 19 1 21 0 00 0 00 1 19 4 78

Dyskinetic event

2 38 0 00 0 00 1 20 0 00 0 00


2 38 0 00 3 58 3 59 1 19 4 78





















Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population


































































































































Placebo (n=75)


Dizziness 8 15 5

Dry Mouth 4 10 1

Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population



















































































































Tachycardia2 6 11 0

Irritability 3 5 0

Arthralgia 1 3 0

Asthenia 1 3 1

Back Pain 1 3 0

Dyspnea 0 3 0


Anorexia 3 1 0

Tooth Abscess 3 1 0

Dyskinesia 3 0 0

Epistaxis 3 0 1











Placebo (n=90)


Dizziness 19 17 2

Nausea 6 10 4

Fatigue 14 9 4


Tachycardia2 6 9 1

Dry Mouth 7 7 0

Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population



















































































































Vomiting 8 7 3



Irritability 3 5 1

Pyrexia 1 4 1

Aggression 1 3 0



Acne 3 2 0

Arthralgia 4 2 1

Lethargy 2 2 0

Pallor 1 2 0


Syncope 2 2 0


Constipation 4 2 0

Ear Pain 2 0 0

Paresthesia 2 0 0








(N=73)

SEROQUEL 800 mgday

(N=74)

All SEROQUEL



Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population



















































































































Parkinsonism 4 55 4 54 8 54 2 27

Akathisia 3 41 4 54 7 48 3 40



2 27 2 27 4 27 0 00



Preferred Term1

SEROQUEL 400 mgday

(N=95)

SEROQUEL 600 mgday

(N=98)

All SEROQUEL



Akathisia 1 10 1 10 2 10 0 00


1 11 1 10 2 10 0 00















7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population




























































































































7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population




















































































































7 DRUG INTERACTIONS











Risk Summary














Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population
































































































































Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population
























































































































Infertility Females
















10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population




























































































































10 OVERDOSAGE





11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population






















































































































11 DESCRIPTION















Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population




























































































































Distribution












Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population






























































































































Coadministered Drug


Drug Quetiapine





150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population




















































































































150 mg twice daily



300 mg twice daily







25 mg single dose



300 mg twice daily



300 mg twice daily



300 mg twice daily



300 mg twice daily




Coadministered drug


drug Quetiapine





150 mg twice daily

















14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population




























































































































14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population





















































































































14 CLINICAL STUDIES












Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population























































































































Study Number




Difference1 (95 CI)

Study 1

SEROQUEL (75 mgday) 457 (109) -22 (20) -40 (-112 33)

SEROQUEL (150 mgday)2 472 (101) -87 (21) -104 (-178 -30)

SEROQUEL (300 mgday)2 453 (109) -86 (21) -103 (-176 -30)

SEROQUEL (600 mgday)2 435 (113) -77 (21) -94 (-167 -21)

SEROQUEL (750 mgday)2 457 (110) -63 (20) -80 (-152 -08)

Placebo 453 (92) 17 (21) -shy

Study 2

SEROQUEL (250 mgday) 389 (98) -42 (16) -32 (-76 12)

SEROQUEL (750 mgday)2 410 (96) -87 (16) -78 (-122 -34)

Placebo 384 (97) -10 (16) -shy

Study 3







Study 4

SEROQUEL (400 mgday)2 962 (177) -273 (26) -82 (-161 -03)

SEROQUEL (800 mgday)2 969 (153) -284 (18) -93 (-162 -24)

















Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population

































































































































Difference2 (95 CI)

Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population



















































































































Study 1

SEROQUEL (200-800 mgday)1 3 340 (61) -123 (13) -40 (-70 -10)

Haloperidol1 3 323 (60) -157 (13) -74 (-104 -44)

Placebo 331 (66) -83 (13) -shy

SEROQUEL (200-800 mgday)1 327 (65) -146 (15) -79 (-109 -50)

Study 2 Lithium1 3 333 (71) -152 (16) -85 (-115 -55)

Placebo 340 (69) -67 (16) -shy



SEROQUEL (400 mgday)1 294 (59) -143 (096) -52 (-81 -23)



ITT population



















































































































































































































































































































































































































































































































































































































































































































Documents

dyslipidemia, and weight gain€¦ · • Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. Appropriate clinical monitoring